Search

Background and state of the art Migraine (M) is the seventh leading cause of years of life lost to disability (YLDs) worldwide, responsible for 2.9% of all YLDs, more than half of all YLDs attributable to neurological disorders [1]. Its negative effects result from several studies, particularly in surveys carried out by our research group, through the application of patient oriented outcome measures (PROMS), and in their development and validation [2-4]. Administration of MIDAS (a migrainespecific tool) demonstrated that: the disability level is rather high (particularly in chronic M); social, family and leisure activities are more impaired than work activities; days spent at work with reduced effectiveness are more than days of absence [3-5]. A better understanding of the pervasive impact of migraine has been achieved using the WHODAS 2.0, a questionnaire based on the International Classification of Functioning, which captures the interaction between the individual’s health status and the context of life. Our data, together with many results deriving from the application of quality of life tools (e.g., SF-36 and MSQ), showed that migraine influences physical and emotional domains, causes restriction and avoidance of activities also outside the headache episodes [6-11].

Background During recent years, various experimental data suggested that the functional state of the migraineur’s brain fluctuates in relation with the cyclical recurrence of the migraine attack. This was historically observed with the methods of clinical neurophysiology that revealed interictal deficient habituation of any kind of sensory responses with the notable exception of the olfaction that was attributed to abnormal thalamo-cortical interactions and its normalization during an attack. On the other hand, studies with repetitive transcranial magnetic stimulation (rTMS), have reported interictal paradoxical cortical responses in reaction to both depressing or enhancing rTMS and their changes up to the bending point of an attack when cortical responsivity behaves differently. Such recurring changes were confirmed recently with morphological and functional neuroimaging methodologies. For instance, fMRI BOLD responses induced by painful stimuli differed between ictal and interictal scans in episodic migraine. We recently showed that cyclic changes can also be demonstrated at rest, i.e. without any sensory input, in anisotropy of thalamic microstructure, in grey matter density of temporo-parietal areas, and in interconnectivity among large scale cortical networks. The conjunction of neuroimaging and neurophysiological data can be considered as robust evidence favouring cycling morphological and functional brain alterations as prominent features of migraine pathophysiology.

Sjaastad & Spierings described “Hemicrania continua” (HC) in 1984[1]. In 2001, succinct criteria were presented[2]: permanent hemicrania, pain intensity: mild-moderate, (but occasionally - severe) and indomethacin dosage < 150 mg daily. In addition, relative shortage of “local” autonomic phenomena, relative lack of “migraine symptoms” and of “cervicogenic” features. Such patients generally had tried legion drugs, with little effect. Such trials equal the usage of placebo. These guidelines seemed to function close to optimally. Then, criteria of the International Headache Society (IHS) (ICHD-III beta classification) came along. Surprisingly, they were transferred from a recent review article by Goadsby[3], almost word by word, despite the existence of a committee of intelligent and knowledgeable colleagues. There is an abundance of failures in the actual scheme. It is unacceptable to include as mandatory criteria, facial/forehead autonomic features. In this way, e.g. sweating becomes prominent - 33%, against a subjective feeling of sweating in only 6% of our series (ratio: 5.5). Objectively, by quantitative evaporimetry, there was no facial asymmetry in all our 8 cases. There were 12 autonomic phenomena in this category[3], with a mean ratio between Goadsby's/our figures of 4.4. When made mandatory, autonomic features will create bogus cases. Bogus cases necessitate ultra-high indomethacin dosages; such dosages have an unspecific, analgesic effect, on various headaches. Our mean indomethacin continuation dosage was: 83 mg (range: 50-150), while in Goadsby's series it was 176 mg (25-500). HC is the unilateral headache with the least “local” autonomic features, “migrainous” and “vascular” components. It is a rather “pure” headache. The present classification brings HC nearer to other unilateral headaches with local autonomic symptoms, a misunderstood policy. CPH is exceptional with clinical similarities; the absolute indomethacin effect suggests a shared, core pathogenesis.

System-wide adoption of Personalised Healthcare requires an active and flexible but highly integrated infrastructure, joining many different competences and technologies and allowing continuous upgrading, also through self-learning processes. In this system, clinics and diagnostics would no longer be partitioned, according to a stepwise scheme, from other disciplines as basic science, information technologies, ethics and policies. Each player constitutes a node of a cabled network, where input and output from each node are automatically transferred to all nodes, to systematically retune and coordinate the global activity. Since 2005 the Sant'Andrea Hospital of Rome is an in-house built model of Personalised Healthcare Service, which auto-catalytically drives its own development, which may furnish good evidence that translation of Personalised Medicine into clinical practice is not so elusive. The interaction between usually distant academic departments and wards (as Biochemistry, Internal Medicine, Psychiatry, Oncology), favoured by a farsighted management of hospital resources by the administrators, allowed to create a shared, innovative laboratory, the Advanced Molecular Diagnostics Unit (DiMA). The availability of advanced technologies, as mass spectrometry and medium-to-high throughput DNA analysis paved the way to a “real-time” evaluation of the benefits brought into the “real-world” clinical practice by implementation of new diagnostics aimed to therapy tailoring. This allowed the start up of a health service based on the principles of personalised medicine, in order to optimize the amount of tests necessary to evaluate the patient, to interpret the results correctly and, finally, to plan a personalised therapy and to periodically evaluate and/or modify it, to obtain the best clinical results with the least side effects. Our OMICS platform for personalised medicine offers the following combined approaches: i) Epigenetics, to obtain information on the regulation of gene expression and to evaluate the methylation profile change during hypomethylation therapies; ii) Functional genomics, to measure genetic expression in normal and pathologic conditions, in order to define genetic expression profiles; iii) Structural genomics, which defines genomic differences with clinical impact in the patient populations; iv) Metabolomics and terapeutic drug managment, to define all molecules of interest in a specific clinical context and the actual drug and metabolite concentration during therapies. The MIFAR (Metabolismo Integrato FARmaci – drug metabolism integration) including about 60 gene variants has been developed. The data interpretation is ruled out using the Charite Bioinformatic platform (Berlin DE) and allows adaptation of drug therapies to the individual MIFAR profile, improving efficacy and safety of treatments. The DiMA Unit provides pharmacogenomics and theranostics report for at least 5,000 patients/year.

The term “chronic migraine” (CM) was officially introduced in 2004 in the second edition of the International Classification of Headache Disorders (ICHD-2), which included it in the chapter on migraine at the three-digit level (code 1.5.1) among the complications of the disorder[1]. The latest edition of the classification (ICHD-3 beta version) published in 2013 still uses the term in the chapter on migraine but moves it to the two-digit level (code 1.3), after migraine without aura (1.1) and migraine with aura (1.2)[2]. According to the ICHD-3, a diagnosis of CM must be made when a patient who has been suffering from migraine for some time has had “headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month”. The major drawbacks in the current systematization of this important chapter are the following: (a) the term used (CM) is ambiguous; and (b) the time pattern indicated in the diagnostic criteria is not adequate to define a homogenous case series of patients. In order to solve these drawbacks and be more adherent to the reality of clinical practice, CM as is currently known should be separated into two parts, depending on the severity of the headache[3]. One thing is having had headache on 15-20 days a month for 3-4 months. Quite another is having had headache each day of the month for several years. In the former case, we could use the term “high-frequency migraine”, including it at the three-digit level of migraine without aura. In the latter case, it would be better if we used the term “transformed migraine”, which is already well known in the literature and should be included at the three-digit level among the complications of migraine. This division of CM as we know it into two separate subgroups could be very helpful both in improving the clinical and healthcare management of patients and in providing much-needed availability of homogeneous case series for basic and pharmacology research. Partly due to the nosographic ambiguities mentioned above, current epidemiological data are still scarce and rather conflicting. Based on the indications from the ICHD-2 and the ICHD-3, CM would have a 1-4% past-year prevalence rate in the general population, showing an even more marked predominance in women than does episodic migraine. More than half the CM cases would also have medication-overuse headache.

According to the existing classification chronic migraine (CM) is a primary headache that occurs on 15 or more days per month for more than 3 months and has the features of migraine on at least 8 days per month. In Europe, CM prevalence ranges from 2.7% to 4.7%. CM is an extremely disabling disorder associated with significant functional impairment. The 2010 Global Burden of Disease Survey conducted by the WHO listed migraine as the 7th cause of disability in the world, responsible for 2.9% of all years of life lost to disability. Unfortunately, however, in its current definition CM includes subgroups of patients with very different levels of severity and outcome. Failing to recognize them entails highly negative repercussions on research and clinical practice, with inadequate patient management and lack of cost-effectiveness. Therefore, it is essential that these subgroups of subjects be clearly identified to optimize clinical management, rationalize the allocation of economic resources, provide specific clinical and health care procedures, and clarify pathogenetic mechanisms. The clinical registry will include the data of all patients with CM, aged 18 or over, seen at the Headache Centres of Parma, Bologna, Rome, and Milan. The diagnosis of CM will be made by a headache specialist based on the diagnostic criteria of the ICHD-III beta (2013) and on the CM classification proposed by Manzoni et al[1]. The principal aim of the clinical registry will be to identify still undefined subgroups of subjects with CM through a specially designed clinical registry to be applied in a large number of outpatients. The registry will make it possible to collect: personal and social patient data, as well as data about their physiological conditions and non-essential habits; clinical features of headache (before and after its evolution to chronicity); any factors concomitant with the headache's evolution to chronicity (i.e., medication overuse, life events, hypertension); comorbidity and injuries; headache-related disability (MIDAS, WHO-DAS-II, MSQ); quality of life (SF36); symptomatic and preventive treatments; medication overuse; visits and hospitalizations for CM; and recognized sickness and invalidity allowances. The creation of a large-scale registry will make it possible to identify specific CM (i.e., refractory CM) subgroups, based on clinical and biological features. It will also make it possible to identify areas with lack of or inadequate health care provision and waste of resources (i.e., useless examinations or treatments), eventually helping to improve CM management and ensure health care procedures that are more appropriate.

Randomisation in clinical trials continues to be controversial and to be attacked on ethical, practical and philosophical grounds. Whatever the practical, moral or philosophical limitations of randomisation may be, many of the attacks reveal that the critics do not understand why randomisation is carried out and what its purpose is. In some cases one may even claim that the defenders of randomisation are equally confused. Seven common myths are examined in this paper, namely, that 1. patients are treated simultaneously in clinical trials 2. balance of prognostic factors in necessary for valid inference 3. observed covariates may be ignored because one has randomized 4. blinding can be carried out effectively without randomisation 5. randomisation is inefficient 6. randomisation precludes balancing covariates and 7. large trials are more balanced than small ones. Many of these myths are related to the problem of distinguishing between conditional and unconditional inference and the relevance of this distinction is explained with a simple game of chance involving two fair dice, and played in three variants, and a statistician who has to correctly call the odds of obtaining a total score of ten. Others simply arise, because many who have written on clinical trials have not designed them. In fact, what some critics have overlooked is that when it comes to allocating treatments to patients, ‘the devil is in the detail’. A useful discipline that can be recommended to any would-be critic of randomisation in clinical trials is to attempt to write a detailed protocol, capable of being followed by another. This ‘thought experiment’ is useful in revealing potential problems with any scheme. Finally a technical problem to do with the estimation of nuisance parameters in analysis of covariance is covered. It is concluded that the debate on the role of randomised clinical trials in evidence based medicine would be improved if those debating it paid careful attention to what randomisation can and cannot do to strengthen the validity of inferences regarding the effects of treatment.

Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin. The evolutionary origin of Plasmodium falciparum, the most prevalent and lethal of the malaria parasites infecting humans, is much debated. Genetic analysis of thousands of fecal samples from wild-living African apes show that the parasites found in the western gorillas — rather than those of chimpanzees or bonobos — are most closely related to the human parasite. The data suggest that all extant human strains of the parasite evolved from a single host transfer event. The new findings are also relevant to the current antimalaria campaign, as they point to potential Plasmodium reservoirs in apes. The evolutionary origin of the human malaria parasite Plasmodium falciparum has been much debated. Genetic analysis of a large number of faecal samples from wild-living African apes now shows that Plasmodium parasites from Western gorillas are most closely related to the human parasite. The data suggest that human P. falciparum evolved from a gorilla parasite after a single host transfer event.

In the closing plenary lecture, Prof Peter Horby describes the challenges of conducting clinical trials in emergency settings.

Various speakers In a combined presentation and discussion session, representatives from academia and industry discuss the role of Biomarker trial design and implementation, to improve health by improving trials.

Liver transplant was introduced as a treatment for Familial Amyloid Polyneuropathy (FAP) in 1990 and since then it was demonstrated that the best results are seen with early onset patients with predominant neurologic involvement (typically Val30Met patients), at the first years of symptomatic disease. Complete stabilization of the neuropathy is seen in a significant proportion of patients. However the treatment introduced mortality and morbidity due to the surgical procedure itself, variable from center to center. Tafamidis, a transthyretin (TTR) stabilizer, administered orally, was approved in Europe in 2011 to treat neurologic involvement of stage 1 patients with any TTR mutation. We have limited long term data on the efficacy of this treatment and after starting treatment we need at least 6 to 12 months to evaluate the impact of the drug on disease progression. This means that choosing Tafamidis first, may significantly delay the option for liver transplant, in case of oral treatment failure, impacting the results of surgery. The choice between these options is not easy because we have not yet enough comparable data. Most patients would prefer to avoid or to delay the need for an aggressive treatment, hoping to be part of the group of good responders to oral medication. How much should doctors point to a given option? Oral treatment should be prescribed as soon as patients develop the first symptoms and signs of neuropathy. Patients diagnosed with advanced stage 1 disease with high probability of being refused for liver transplant in one year should be sent directly to surgery. If the waiting time is less than one year the benefit of receiving Tafamidis while waiting must be weighted. Patients with more advanced neurologic disease and/ or important cardiac involvement should be considered for clinical trials or for other drug treatments. Published: 2 November 2015

Results We found that CNS clinical involvement occurs in FAP patients that underwent liver transplantation (LT). Patients exhibited positive and negative FNEs clinically similar to the recently described “amyloid spells” characteristic of Ab related cerebral amyloid angiopathy (CAA) patients. Longer disease duration, male gender and renal dysfunction were associated with the presence of FNEs in FAP patients after LT. In post-mortem brain analysis, FAP patients exhibit prominent CAA associated to progressive TTR meningeal-vascular deposition, that progressed from the meninges and its vessels towards meningo-cortical vessels and the superficial brain parenchyma, as disease duration increased. Neuroimaging findings (lobar brain hemorrhage, localized subarachnoid hemorrhage and white matter damage) also support that TTR related CAA contributes to this new clinical phenotype. Conclusions Both the clinic presentation and the topography of the neuropathological abnormalities of FAP patients with this new CNS phenotype overlaps to what is known to occur in sporadic Ab-associated CAA. Moreover, neuroimaging findings in such patients suggest that CAA may be a leading player, hinting that these two pathologies could also share devastating consequences (brain hemorrhage, localized subarachnoid hemorrhage and, eventually, cognitive decline). Given the hemorrhagic risk of these vasculopathies, our results have implications in the treatment and clinical follow-up of FAP patients. In addition, sensitive imaging methods (e.g. MRI) need to be implemented in the study of ATTR patients presenting FNEs. Present and future disease modifying therapies should consider CNS TTR deposition as a target.

Background The Transthyretin-Familial Amyloid Polyneuropathy (TTR-FAP) is a disease caused by deposition of mutant transthyretin (TTR), produced approximately 95% in the liver and the rest in the plexus choroideus and retina. In 1990 the first TTR-FAP patient liver transplant was performed. The liver transplant, which suppresses TTR synthesis, was the only treatment available to modify this disease until 2011, when the European Medicines Agency approved Tafamidis, a TTR stabilizer, for stage I patients (Val30Met and non-Val30Met). To improve upon the pre-existing therapy of liver transplants and given the results of 68% of Tafamidis respondents, other disease-modifying therapeutic approaches were developed: Silencers, Stabilizers, Degraders and Reabsorption agents. In light of these multiple agents clinical trials are the key to improve TTR-FAP treatment.

Familial amyloidosis typically causes a nerve length-dependent small fiber polyneuropathy that starts in the feet with loss of temperature and pain sensations, associated with autonomic dysfunction, which can be extremely severe and life threatening. Neuropathic pain is commonly associated with amyloid neuropathy. There are no randomized controlled trials in peripheral neuropathies specifically related to familial amyloidosis. However meta-analyses have confirmed that the efficacy of drugs against neuropathic pain generally is not linked to the aetiology of pain and therefore the drugs found effective in other painful polyneuropathies may benefit to patients with amyloid neuropathies [1]. Recently the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain has updated evidence-based recommendations for pharmacotherapy of neuropathic pain [1] using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Pregabalin, gabapentin, serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants particularly duloxetine, and tricyclic antidepressants (TCAs) received strong GRADE recommendations for use and are recommended as first-line for peripheral neuropathic pain, although with caution as regards TCAs. Capsaicin high concentration patches, lidocaine patches and tramadol received weak GRADE recommendation for use and are recommended as generally second line for peripheral neuropathic pain and local pain generator. Strong opioids and botulinum toxin type A (BTX-A received weak GRADE recommendations for use mainly because of efficacy in most trials but safety concerns (opioids) or lower quality of evidence (BTX-A). These drugs are recommended as third line by specialist use as regards BTX-A. There was a weak GRADE recommendation against the use of oromucosal cannabinoids (Sativex) and valproate and strong GRADE recommendations against the use of levetiracetam and mexiletine because of generally negative results and safety concerns (mexiletine). Other drug treatments (e.g. other antiepileptics, antidepressants and topical treatments, tapentadol and NMDA antagonists) or combination therapy received inconclusive GRADE recommendations because of generally discrepant findings, although some of these drugs might be effective in subgroups of patients. These drugs can be recommended in familial amyloid neuropathy, but topical agents have a major advantage in this context because of their low risk of systemic side effects.

Fifty years ago, the focus on the Val30Met type of the disease, in which neurologic manifestations predominate, led to the widespread notion that hereditary transthyretin-related amyloidosis (ATTR) was essentially a neurologic disease. It is now clear that ATTR is extremely heterogeneous on both genotypic and phenotypic grounds. The clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to strictly cardiac manifestations. This heterogeneity is linked to several factors including specific transthyretin mutations, geographic distribution and endemic vs. non-endemic aggregation type. The existence of exclusively or predominantly cardiac phenotypes makes the recognition of the disease very challenging since it can mimic other more common causes of left ventricular “hypertrophy”. Assessment of such patients should include an active search for possible red flags that can indicate the correct final diagnosis. More in general the clinician must be aware that: • Cardiac amyloidosis (CA) should be suspected in any patient with heart failure, unexplained increased LV wall thickness and non-increased end systolic left ventricular volume • In a patient with an initial diagnosis of hypertrophic cardiomyopathy (HCM), look for the infiltrative phenotype hidden beneath the hypertrophic one! • A distinctive sign of CA is the abnormal ratio between left ventricular thickness and QRS voltages rather than low QRS voltages, alone. The absence of low QRS voltages doesn’t rule out a CA if the context is otherwise fitting and up to 20% of subjects with CA can have electrocardiographic evidence of left ventricular hypertrophy. • In an elderly man with unexplained concentric left ventricular hypertrophy, especially in the absence of hypertension, always consider the possibility of wtTTR CA! • Amyloidotic cardiomyopathy in an elderly patient with monoclonal gammopathy is not necessarily related to AL: consider the possibility of wTTR + MGUS • Longitudinal LV function can be severely depressed despite a normal LVEF and the myocardial contraction fraction is often low suggesting reduced global myocardial shortening. • Myocardial deformation is reduced in amyloidotic cardiomiopathy but the apex is generally spared • In CA, Gadolinium distribution at MRI is heterogeneous: subendocardial late gadolinium enhancement (LGE) is not the only diagnostic pattern and the absence of LGE does not exclude CA. • Bilateral carpal tunnel syndrome in a man with HCM-like phenotype on echo is highly suggestive of TTR-related CA The natural history of ATTR is only partially known, due to the rarity of the disease and its high genotypic heterogeneity. Patients with ATTR cardiomyopathy have a much more indolent course than those with AL etiology. Progression of neurological disease and heart failure are the leading causes of death. As in AL amyloidosis, in ATTR the presence of cardiac involvement is an incremental risk factor for overall and cardiovascular events. Consequently, non-Val30Met mutations, in which cardiac involvement is more frequent and severe, appear to be associated with a particularly poor prognosis, even after successful OLT . Very little is known about the underlying cause and the incidence of sudden death, which has been reported to be associated with the occurrence of advanced atrioventricular blocks, ventricular tachycardia/fibrillation, or, probably more frequently, electromechanical dissociation.

Genetic counselling is “a process of communication that deals with the occurrence, or risk of occurrence, of a (possibly) genetic disorder in the family” (ASHG, 1975; EuroGentest guidelines). It involves an attempt, by appropriately trained persons, to help patients and their families to (1) understand the medical facts of the disease; (2) appreciate the contribution of heredity and risks of recurrence in relatives; (3) understand the consultands’ options to deal with those risks, including all their reproductive options; (4) use this genetic information in a personally meaningful way that promotes health, minimizes psychological distress and increases personal control; (5) choose the course of action that seems appropriate to them and act in accordance with that decision; and (6) make the best possible adjustment to the disease or the genetic risks (modified by EuroGentest Unit 3 from Frazer, AJHG 1974; Biesecker & Peters, AJMG 2001; Harper, 2012).

A strict relationship between migraine and psychiatric factors has been suggested, but the exact role and the influence on evolution of headache is unknown. The most frequent diagnosis was a comorbidity of anxiety and mood disorders. The comorbidity of psychiatric disorders and headache has important implications as far as treatment is concerned. In comparing DSM-V, ICHD-3β and ICD10 criteria on headache and psychopathology, diagnostic criteria agree on pre-existing headache with the characteristics of a primary headache disorder becoming chronic, or made significantly worse, in close temporal relation to a psychiatric disorder, both in the initial headache diagnosis and psychiatric diagnosis. Headache attributed to psychiatric disorder should be given, provided that there is good evidence that that disorder can cause headache. When a causal relationship cannot be confirmed, the pre-existing primary headache and the psychiatric disorder are diagnosed separately. Thus, the diagnostic categories are limited to those few cases in which a headache occurs in the context and as a direct consequence of a psychiatric condition known to be symptomatically manifested by headache. Diagnostic criteria must be restrictive enough not to include false positive cases, but must set the threshold low enough to admit the majority of affected patients. Headache disorders occur coincidentally with a number of psychiatric disorders. Although criteria for headaches attributed to psychiatric disorders have suggested that headache occurring exclusively in association with several common psychiatric disorders, such as, depressive, anxiety and trauma/stress-related disorders, might be considered as attributed to these disorders, because of uncertainties concerning the causal relationships and relative lack of evidence in this context. Evidence suggests that the presence of a comorbid psychiatric disorder tends to worsen the course of migraine and/or tension-type headache by increasing the frequency and severity of the headache and/or making it less responsive to treatment. Thus, identification and treatment of any comorbid psychiatric condition is important for the proper management of these headaches. It should be noted that somatization disorder per se is not included in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), it has been replaced by the category Somatic Symptom Disorder, characterized by one or more somatic symptoms. Thus, ICHD-3 beta continues to refer to the DSM-IV definition of somatization disorder. Using WHO's criteria and methods for measuring burden of disease in DALYs, headache disorders can be placed correctly in the context of other mental and neurological disorders and other chronic illnesses. In order to know the full burden attributable to headache disorders, however, further epidemiological work must be conducted around the world and this must encompass assessments of clinical, economic and humanistic impacts.

Primary headaches are common debilitating disorders with high prevalence and significant socioeconomic and personal impacts. Idiopathic headaches affect all aspects of the individual's life and are the result of complex interaction of biological, psychological, and environmental factors. In patients with chronic headaches the efficacy of pharmacological treatments is often not satisfactory. Pain and disability can potentially induce an escalation of analgesics/triptans intake leading to medication-overuse headache [1]. Experiencing pain can trigger a cascade of neurological events that lead to an altered psychological state and therefore to aberrant behaviors. Moreover, prior psychological states and psychiatric comorbidities can confer a heightened risk for pain chronicity due to processes such as cross sensitization, where exposure to stress in the past results in greater sensitivity to other seemingly unrelated stimuli[2]. Accordingly, the processes of sensitization in headache patients, can be expressed both in the peripheral and central nervous systems, contributing to pain chronicization. Given the multidimensional nature of chronic pain, efficacious assessment and treatment requires a comprehensive, multiaxial approach considering every aspect of the individual's life[3, 4]. Modification of lifestyle habits could play a role in preventive strategies of primary headaches, especially in childhood and in adolescence[5]. The non-pharmacological therapies can be part of a multimodal treatment or an alternative therapy in the case of pregnancy, breast feeding, multiple therapies for comorbid diseases, poor tolerability of drugs, childhood and elderly[6]. Acupuncture and biofeedback are considered the first-choice for the prophylaxis of tension-type headache[6]. Many other non-pharmacological treatments are useful in the prevention of primary headaches, although further well-conducted studies are needed to support their efficacy. They include physiotherapy/physical exercise, progressive muscle relaxation training, short-term psychotherapy and cognitive-behavioural therapy[6]. Another promising intervention is Mindfulness meditation, which is characterized by deliberately focusing on the present moment in a non-judgmental way[7]. Several recent neuroimaging studies suggest that meditation may modulate pain through several mechanisms[8]. It may reduce the saliency of noxious stimuli through attentional focusing, and promote pain modulation reducing expectations of impending noxious stimuli. Moreover, it could induce beliefs related to the promotion of pain relief and refraining from catastrophic thinking. The headache patient can be difficult to manage. We propose the setting of a multimodal treatment, shared by the patient who has to be considered an integral part of care, aimed at improving all aspects of the individual's life.

The pathogenesis of chronic migraine (CM) remains largely unknown. We hypothesized that anomalies of tyrosine metabolism, found in migraine without aura (MwoA) patients, play an important role in the transformation of MwoA into CM, since the increase in the number of MwoA attacks is the most predisposing factor for the occurrence of CM. To test our hypothesis we measured the plasma levels of dopamine (DA), noradrenaline (NE) and trace amines, including tyramine (TYR) and octopamine (OCT), in a group of 73 patients with CM, 13 patients with chronic tension-type headache (CTTH) and 37 controls followed in the Headache Centres of the Neurology Departments of Asti, Milan and Vicenza hospitals in Italy. The plasma levels of DA and NE were several-fold higher in CM patients compared with control subjects (p > 0.001). The plasma levels of TYR were also extremely elevated (p > 0.001); furthermore, these levels progressively increased with the duration of the CM. Our data support the hypothesis that altered tyrosine metabolism plays an important role in the pathogenesis of CM. The high plasma levels of TYR, a potent agonist of the trace amine associated receptors type 1 (TAAR1), may ultimately down-regulate this receptor because of loss of inhibitory presynaptic regulation, therein resulting in uncontrolled neurotransmitter release. This may produce functional metabolic consequences in the synaptic clefts of the painmatrix implicated in CM. Written informed consent to publication was obtained from the patient(s).

Osmophobia (Os), defined as a perception of odors as unbearable during the headache attacks, has been described since ancient times as an accompanying symptom of migraine. More recently authors demonstrated that Os is much more relevant in migraine patients (M), with (MA) or without aura (MO), than in various primary headaches (PH). It has also been put in evidence that Os is very specific in the differential diagnosis between M and tension-type headache (TTH). Consequently, the 2004 edition of ICHD included in the Appendix (A1.1) Os among the proposed alternative diagnostic criteria of MO. In January 2013, a provisional revised version (ICHD-3 beta) of the previously released classification was offered for the approval of the scientific community. In this version Os disappeared from the Appendix, without any explanation.

The impact of headache disorders is a problem of enormous proportions, both for the individual and the society. Medical literature has tried to assess its effects on individuals, by examining prevalence, distribution, attack frequency and duration, and headache-related disability, as well as effects on society, looking at the socio-economic burden of headache disorders. The issue of costs represents an important problem too, concerning both direct and indirect costs. Direct costs concern mainly expenses for drugs. Migraine has a considerable impact on functional capacity, resulting in disrupted work and social activities: many migraineurs do not seek medical attention because they have not been accurately diagnosed by a physician or do not use prescribed medication[1]. Indirect costs associated with reduced productivity represent a substantial proportion of the total cost of migraine as well. Migraine has a major impact on the working sector of the population, and therefore, determining the indirect costs outweighs the direct costs. This study will explain the notion of cost of illness, examining how it could be applied in such a framework. Then, an overview of the studies aimed at measuring direct and indirect costs of migraine and headache disorders will be carried out, later shifting on to the relationship between costs and quality of life for people affected by headache disorders. As it has been seen, there are still many unsolved problems in disease costing, to the point that it still appears as a set of method that may lead to extremely different outcomes depending on the evaluation approach being used. Moreover, given the social relevance of migraine, together with the assessment of therapeutic options, it is important to increase the knowledge related to the economic consequences of prevention. From the analysis of prevalence, incidence, morbidity and the state of health caused by headache, it is important to stimulate the scientific community and policy makers to analyze the problems connected to the economic costs of headache. Costs of headache could be contained by observing their trends implementing specific “observatories”. Overall, the bottom-up approach, applied in the Eurolight study, would seem the preferable and most comprehensive method to assess the societal burden of headache. However, a crucial factor is the attainment of a higher participation to the survey.

In predisposed subjects with migraine or tension-type headache increasing intake of acute medications is associated with a progressive clinical worsening. When the days of symptomatic drug use reach a given threshold (10 or 15 days/month, depending on the classes of drugs, ICHD-III) and the headache has become chronic for at least three months, a causal relationship is deemed to exist between the medication overuse and the clinical worsening, and the headache is termed medication-overuse headache (MOH). MOH affects nearly 2% of the general population. It represents a highly disabling condition that impacts considerably on the quality of life of sufferers and on the society in general because of high levels of disability and use of healthcare resources.

Calcitonin gene-related peptide (CGRP) seems to play a major role in migraine mechanism. Overwhelming data report the efficacy of small molecule CGRP receptor antagonists in the treatment of migraine attacks. If some CGRP receptor (CGRP-R) antagonists could theoretically cross the blood brain barrier (BBB) one of them, olcagepant, due to its peptoid nature could not. However, the clinical development of such otherwise well tolerated compounds has been spoiled by their hepatic liability that has been considered an off-target effect. In the last few years the identification of monoclonal antibodies (Ab) for CGRP or the CGRP-R has provided an alternative strategy to maintain a good efficacy profile and circumvent the severe liver toxicity of classical small molecules CGRP-R antagonists. Indeed, data from phase-II trials are showing that the therapeutic gain between active treatment with the various anti-CGRP Abs and placebo varies from about 20% to 40% and adverse reactions are limited to irritation at the site of injection and few other minor effects. Anti-CGRP mAbs predictably may cross the BBB at a minimum extent, thus making unlikely the hypothesis that they act at sites of action within the central nervous system. This observation is associated with the prevalent localization of the complex multimeric assembly of CGRP-R in the vascular smooth muscle where they mediate the inflammatory neurogenic vasodilatation. Thus, the most parsimonious hypothesis proposes that blockade of the CGRP/CGRP-R receptor system within the cranial neurovascular system produces the desirable analgesic effect in migraine pain. If the mechanism and the genetic background that by promoting cranial neurogenic vasodilatation generate migraine pain remain a mystery, some insights on the triggers that may activate this pathogenic pathway are now better understood. A series of agents known to provoke migraine attacks have been identified as activators of certain transient receptor potential (TRP) channels expressed by a subpopulation of peptidergic nociceptors. In particular, the subtypes ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are activated by migraine provoking agents. Nitric oxide, umbellulone and acrolein gate TRPA1 and alcohol TRPV1. All stimuli by channel targeting generate CGRP release from perivascular terminals of cranial sensory neurons, thus producing the neurogenic effect blunted by CGRP-R antagonists and by anti CGRP mAbs. More importantly, antimigraine medicines, such as metamizole (dipyrone), propyphenazone and parthenolide exert their analgesic effect by antagonizing TRPA1.

Fibromyalgia is a chronic pain syndrome of unknown etiology characterized by diffuse pain, sleep disorders, fatigue, cognitive dysfunction and a cohort of different symptoms implying comorbidity with diseases with common pathophysiological basis. There is a growing body of evidence that abnormal pain processing at a central level has a role in FM pathogenesis, though recent evidence supports the coexistence of a peripheral nociceptive fibers sufferance. In recent years, clear phenomena of temporal summation of pain (or windup) and central sensitization have been extensively reported. Neurophysiologic methods able to explore the nociceptive afferent system suggest that FM syndrome is heterogeneous, with pain processing dysfunction at both peripheral and central level. Reduced habituation to multimodal and especially painful stimuli characterizes FM, as well as associated conditions, one of the most common is migraine. A genetic dysfunction of ionic channels may possibly explain neuronal abnormalities at both central and peripheral level in FM, opening a new scenario also in the comprehension of pathophysiological basis of associated conditions.

In most studies, episodic migraineurs have an interictal habituation deficit of cortical evoked potentials to repeated monotonous stimuli. It has been found by applying almost every modality of sensory stimulation for evoked potentials (visual - VEP, auditory - AEP, somatosensory - SEP), as well as in visual evoked magnetoencephalographic (MEG) responses[1], thus it is considered as a biomarker of the interictal status, which normalises during the migraine attacks and cannot be found in chronic migraine. A reduced habituation deficit, however, was not confirmed in migraineurs in some studies[1], which was attributed to low reliability and repeatability[2, 3], and to a reduced specificity to migraine pathophysiology. Nonetheless, some studies that demonstrated an interictal deficit of cortical habituation were conducted blindly, both for VEP[4, 5] and AEP[6]. Moreover, when the same VEP data were analysed independently by two investigators, one of them totally blinded to the diagnosis and the migraine state (ictal vs interictal), blinded and non-blinded analyses were strictly intraindividually correlated and both confirmed the presence of interictal deficit and ictal normalization of VEP habituation. Repeated intraindividual recordings were also strictly correlated, which suggests a good test repeatability[7]. The habituation deficit in VEP has been demonstrated up to now only in pediatric photosensitive epilepsy (which may share some cortical abnormalities with migraine)[8] and in healthy subjects with a high analytic score[9], suggested to be increased in migraineurs[10]. Although the latter may play a role in the habituation deficit found in migraineurs, it cannot explain its variations during the migraine cycle and its absence in chronic migraineurs. On the other hand it has been demonstrated that at least two different electrophysiological phenotypes may be found in migraineurs[11] and that the deficit of VEP habituation may be slightly different when the same tests are performed in different countries[12]. The discrepant findings in the literature can thus most likely not be explained by the presence or absence of blinding nor by low repeatability. Other methodological issues might be responsible, such as, for instance, online averaging - commonly used in the “negative” studies - that is associated with short interruptions of the visual stimulation, possibly allowing a recovery of habituation. Also, the recruitment of patients, usually performed in headache centers in the “positive” studies, may have contributed to a better selection of patients. Alternatively, phenotypic and/or genotypic differences in cohorts of patients could result in different neurophysiologic patterns.

Kynurenine pathway (KP), the quantitatively main branch of tryptophan metabolism, has long been considered a source of nicotinamide adenine dinucleotide, although several of its products, the so-called kynurenines, are endowed with the capacity to activate glutamate receptors, thus potentially influencing a large group of functions in the central nervous system (CNS). In fact, Kynurenic Acid and Quinolinic Acid are able to interact with ionotropic glutamate receptors and Cinnabarinic Acid has been reported as an orthosteric agonist of metabotropic glutamate receptors (mGlu4), and Xanthurenic Acid has been recently demonstrated to be a putative agonist of metabotropic glutamate receptors 2/3 (mGlu2/3). Moreover, 3-HK and 3-HANA have mainly been studied, since they have been shown to induce neurotoxic effects by increasing oxidative stress and the production of free radicals or through excitotoxicity. Migraine has a complex pathophysiology in which both central and peripheral components of the trigeminal pain pathway play a central role. The trigemino-vascular activation during the attack has largely been described, and recently the brainstem nuclei, called “migraine generators”, have been reported to be involved in migraine. Moreover, a series of destabilizing events within the brain trigger a cortical spreading depression (CSD), responsible for the aura phenomena and for trigeminal activation. The role of glutamate is heavily supported both in the trigemino-vascular as well as in brainstem nuclei activation, and furthermore in the CSD initiation and propagation. Some of the KP metabolites able to interact both with ionotropic and metabotropic glutamate receptors might be involved in migraine pathophysiology. Despite the large number of studies conducted on migraine etiopathology, the KP has only been recently linked to this disease. Nonetheless, some evidence suggests an intriguing role for some kynurenines, and an exploratory study on the serum kynurenine levels has been helpful to better understand possible alterations of the kynurenine pathway in patients suffering from migraine.

In past years, several studies evidenced neurophysiologic dysfunctions in sporadic episodic (during both the ictal and the interictal period), and chronic migraine patients. These dysfunctions could reflect a genetic susceptibility that exposes patients to recurrence of migraine attacks. Recently, several studies were performed in order to explore the role of genetic polymorphisms on neurophysiologic dysfunctions that were already known to be related to migraine. These studies evidenced that neurophysiologic features, such as interictal habituation deficit and ictal response sensitization, are influenced by genetic polymorphisms involved in neural plasticity (brain derived neurotrophic factor [BDNF]), in vascular homeostasis (angiotensin converting enzyme [ACE] and methylenetetrahydrofolate reductase [MTHFR]), and in monoaminergic modulation (monoamine oxidase type A [MAO-A]). Moreover, we have recently found that a glutamatergic polymorphism, Glutamate receptor ionotropic AMPA 3 (GRIA3), already known to be related to central sensitization mechanism and then to migraine pathophysiology, can also influence neurophysiologic features of chronic migraine due to medication overuse. The study of the influence of genetic polymorphisms on migraine-related neurophysiological dysfunctions could be regarded as an “in vivo” human experimental model in which the different genetic background could predict different neurophysiologic “endophenotypes”. This experimental model could lead to understand, for instance, the way different drugs act on migraine, or to unveil in which way some risk factors, such as for instance drug overuse, induce transformation from episodic to chronic migraine.

The molecular and cellular mechanisms of the primary brain dysfunction leading to the onset of a migraine attack and to susceptibility to cortical spreading depression (CSD), the neurophysiological correlate of migraine aura and a likely trigger of the headache mechanisms, remain largely unknown and major open issues in the neurobiology of migraine. Our approach to these open questions is the study of the functional consequences of mutations causing familial hemiplegic migraine type 1 and type 2 (FHM1 and FHM2). FHM1 is caused by gain-of-function mutations in the neuronal CaV2.1 channel, a voltage-gated calcium channel that plays a dominant role in controlling neurotransmitter release at brain excitatory and inhibitory synapses. FHM2 is caused by loss-of-function mutations in the glial alpha2 Na/K-ATPase, an isoform that is thought to have specific roles in K+ and glutamate clearance by astrocytes and in astrocyte Ca2+ homeostasis. Knockin (KI) mouse models carrying FHM1 or FHM2 mutations show a lower threshold for CSD induction and a higher velocity of CSD propagation. We have investigated the cortical mechanisms underlying the facilitation of experimental CSD in FHM1 and FHM2 KI mice by studying synaptic transmission at cortical excitatory and inhibitory synapses and the rate of glutamate and K+ clearance by cortical astrocytes in acute cortical slices. Our findings are consistent with the conclusion that increased activation of NMDA receptors due to enhanced cortical glutammatergic synaptic transmission in FHM1 and to reduced rate of glutamate clearance at cortical excitatory synapses in FHM2 contributes to the facilitation of CSD in FHM KI mice. The data from FHM mouse models support the view of migraine as a disorder of brain excitability characterized by dysregulation of the excitatory-inhibitory E/I balance, and point to episodic disruption of the E/I balance and neuronal hyperactivity due to excessive recurrent glutammatergic transmission as the basis for vulnerability to CSD ignition in FHM.

Chronic migraine (CM), a highly disabling condition affecting 2-3% of the general population, represents a difficult-to-treat disorder for its unclear pathophysiology, complex comorbidities, and disappointing response to available pharmacological treatments[1]. High quality evidence (≥2 RCTs) recommends the prophylactic use of onabotulinum toxin A (155-195 IU) and topiramate (100 mg) in CM, while lower quality evidence (1 RCT) supports the treatment with sodium valproate (800-1500 mg), gabapentin (2400 mg) and tizanidine (18 mg)[2]. Amitriptyline, memantine, zonisamide and pregabalin may also be of help in CM but their use has been suggested only in open studies[2]. CM patients may show poor or no response to preventative therapies. The consensus statement of the European Headache Federation (EHF) defines CM refractory to treatment (rCM) when it does not respond to adequate dosages of at least 3 drugs from the classes of beta-blockers, anticonvulsants, tricyclics, onabotulinum toxin A and others (e.g., flunarizine, candesartan) for at least 3 months each, in absence of medication overuse[3]. This rCM definition has been questioned by some authors who stressed the need of using drugs from different classes, not limited to 3, before making rCM diagnosis[4]. Labeling a patient as affected by rCM may profoundly modify his/her life with heavy psychological, social, work and medico-legal consequences, potentially leading to expensive and still unsatisfying surgical procedures such as occipital nerve stimulation[5]. We point out the risk that the current rCM EHF definition could indeed also include pseudo-refractory CM patients, due to potential bias: firstly, a significant proportion of CM patients may spontaneously reverse to episodic migraine, as clearly evidenced in population-based study[6]; secondly, rCM patients may present underlying psychiatric disturbances (e.g., personality disorders) not easily recognized, classified and treated by headache specialists; thirdly, rCM diagnosis could be biased by unproven evidence as current rCM criteria do not specify who should attest patient's previous headache history (theoretically self-reported or stated by unqualified physicians). We suggest that 1) rCM is probably more rare than presently stated; 2) before formulating a diagnosis of rCM, psychiatric disorders should be carefully ruled out by appropriate and thorough psychiatric investigations; 3) when assessing CM patient's past medical history, only clinical data coming from certified headache centers should be considered; 4) CM patients should be followed up for an adequate period of time before making a definite rCM diagnosis.

Migraine with (MA) and without aura (MO) is a common brain disorder that affects 15% of the general population. Genetic studies on twins have shown that MA and MO heritability spans between 50% and 60%[1]. Despite the high degree of heritability the genetic basis of MA and MO has not been elucidated and on the whole their etiology is far from being resolved. Several years ago it has been hypothesized that also epigenetic mechanisms such as DNA methylation, miRNA and histone modifications could play a relevant role in MA and MO. In particular epigenetic mechanisms have the potential to link early life events, neuro-inflammation and estrogen activities in the etiology of migraine and in its chronification[2] and pharmaco-epigenetics could be implicated in the wide spectra of different drug treatment responses[3]. In recent years the technologies for studying nucleic acids have literally exploded, opening to new possibilities for study of genetics and epigenetics of MA and MO[4]. One of the most significant results is the sharp cost decrease for the whole genome DNA sequencing, since the psychological threshold of 1000$ for a 30X genome is about to be achieved. This cost reduction is fostering a wealth of large sequencing campaigns that will allow overcoming all the limitations due to the poor knowledge of human genetic variability that has plagued the ability of identifying the genetic basis of all sporadic diseases including MA and MO[5]. The reduction of nucleic acids sequencing costs and the availability of cost effective microarray solutions for the analysis of DNA methylation has favored the implementation of epigenomic studies, in particular DNA methylation microarray has been thoroughly used providing new insight regarding the variability and the role of such epigenetic agent. DNA methylation, miRNA and histone modifications have proven to be a potential source of powerful and robust biomarkers. Taken together both the new genetic and epigenetic omic approaches have the potential to provide new molecular insight in the etiology of MA and MO. Moreover from such approaches we expect to obtain tools to improve migraine diagnosis, patient stratification, and therapy.

Neurostimulation has been used in pain management for a long time. Several neuromodulatory surgical techniques were developed to manage headaches unresponsive to medical treatment, in particular for preventive treatment. Recently, novel non invasive neurostimulation approaches have been used successfully for different forms of headache: they represent a promising opportunity in headache management useful for acute and preventive treatment of migraine. Among the different non invasive approaches, transcutaneous supraorbital electrostimulation device (Cefaly), transcutaneous magnetic stimulation (TMS), transcranial electrical stimulation (t DCS), and non-invasive vagus nerve stimulation device (n VNS) have shown efficacy in a consistent number of pilot studies (lack of placebo condition). Vagus Nerve Stimulation (VNS) was a well known surgical procedure approved for treatment of refractory epilepsy and depression, with a peripheral mechanism of action. It has been used in selected intractable migraine cases if associated with comorbid depression, with promising results. A hand-held patient controlled non-invasive vagus nerve stimulation device (Gammacore) has been developed to treat migraine attack and has contributed to an easier treatment of migraine episodes. Goadsby et al reported significant results from treatment of migraine attacks by non-invasive transcutaneous vagal nerve stimulation in a population of 30 patients with a 2-hour pain-free rate of 22%. In our open-label, single arm, multiple attack, 27 patients, 18-65 years old, with a diagnosis of migraine without aura according to the IHS beta 2013 classification, with a high frequency, were enrolled and participated in the study with 112 attacks treated. Treatment consisted of one stimulation, 90-second dose, delivered to the right cervical branch of the vagus nerve. In forty-four attacks (39.2%) 9 resolved within 30 minutes; 50 attacks (44.6%) did not resolve in the first 2 hours, so patients used rescue medication; in 18 attacks (16.2%) there was no complete resolution of pain, but a significant relief in the first 2 hours (40% in the VAS scale) and patients did not use any rescue medication. No adverse events were recorded, the therapy was well tolerated. Non-invasive vagus nerve stimulation (nVNS) offers a novel approach to acute migraine attack. For patients with high frequency of migraine attacks, nVNS may represent a suitable tool to decrease the risk of medication overuse. The variety of non-invasive neuromodulatory approaches has opened new strategies for treatment of patients suffering from drug-refractory forms of headache. Randomized sham controlled studies and larger and multicentre trials are needed in order to determine the optimal dosage and to clarify the mode of action.

The use of diagnostic imaging in the evaluation of patients with headache is an almost mandatory step. Although there are specific conditions (the so-called red flags) indicating the need of diagnostic imaging, daily experience shows that a study of the brain and, often, of the intracranial vessels, is part of the routine of many of these patients. The most common and appropriate study is the MRI integrated with the angiographic evaluation (MRA). An MRI and MRA, properly performed, are able to exclude most of the organic pathologies potentially causing headache. The list of these conditions is long and not useful in this context. It is important to remember that significant MRI changes are found in about 4% of patients with chronic headache but this percentage can rise up to 14% in the atypical forms. The MRI evaluation also allows to define whether the patients, especially the young ones, have a condition of brain signal alterations (multiple bright spots). Some studies reported that these are more frequent in patients with migraine especially with aura and mostly in females. The clinical significance and role of these changes remains to be proven. Another approach of imaging is related to the possibility of assessing, by means of functional studies, the pathophysiological moments responsible for the symptoms. These studies are based mainly on functional MRI which includes cerebral perfusion, cortical activation (induced or by means of resting state techniques) and metabolic studies with spectroscopy. The last approach is the one that assesses the consequences of long standing symptom analyzing morpho-volumetric brain “in toto” or inside the cerebral cortex. These are techniques like computed voxel based morphometry (VBM) or Free Surfer able to evaluate small volumetric changes between groups of healthy subjects and patients.

Processing of sensory stimuli has been supposed to be dysfunctioning in migraine. A basis for such abnormality has been identified in a defective ability to habituate to repetitive sensorial stimulation. Habituation, i.e. the way the nervous system attenuates response to repeated non noxious stimuli is a fundamental function of sensory systems, that allows appropriate adaptation of neural responses to the relevance of incoming stimuli. In humans, habituation can be studied by evoked potentials where it is indexed by a reduction of amplitude of the evoked response to repeated stimulation. After the first evidence by Schoenen et al in 1995[1] of reduced habituation to visual evoked potentials in migraine the defect was confirmed in other studies, not only with visual stimuli, but also with other sensory modalities (acoustic, somatosensory) and even with nociceptive stimulation. For such a consistency lack of habituation has been considered a neurophysiological hallmark of the disease. However, critical aspects concerning this statement have been recently raised because the requirement for a disease hallmark appeared not to be met by lack of habituation[2, 3]. A disease hallmark should be intrinsic to the pathophysiology of a disease and as such ubiquitous or quite so and specific for that disease. This however, does not seem to be the case for lack of habituation in migraine. Some authors indeed were not able to find defective habituation in this disease and recently relevant criticism about this dysfunction has been raised by the group of Sand and Omland[2]. These authors indeed applying a different methodological approach (with a blind procedure for both VEP recording and analysis) in a series of studies (exploring a wide range of stimulation parameters) were not able to replicate, at least for visual modality, the habituation defect and attributed this to a likely expectancy bias not adequately controlled in previous studies. Moreover, dysfunctioning habituation is not specific for migraine as it has been found in several other diseases ranging from chronic pain states, to deafferentation diseases like tinnitus, or degenerative pathologies like Parkinson's disease. Thus, more than strictly related to migraine pathophysiology, lack of habituation could represent a more general marker of neural dysfunction that migraine can share with several other diseases.

Although headache represents the main symptom of migraine, it is a very complex disease and can be manifested by a number of other symptoms. This is particularly evident in pediatric age where clinical conditions different from headache can involve children who are already suffering or will suffer from migrainous headache. In the International Classification of Headache Disorders 3rd edition (ICHD-III), these conditions, occurring as repeated attacks with complete remission between episodes, are defined as “Episodic syndromes which may be associated with migraine”. They include “Cyclical vomiting syndrome” (1.6.1.1), “Abdominal migraine” (1.6.1.2), “Benign paroxysmal vertigo” (1.6.2) and “Benign paroxysmal torticollis” (1.6.3). Though not included in the ICHD-III, other clinical entities, such as motion sickness and limb pain, have been associated with migraine. In order to underline the strict relationship between all these non headache symptoms and migraine, they are also known as “migraine equivalents”. We investigated the migraine equivalents prevalence in a large population of children referred to our pediatric headache centre[1]. A total of 1,134 of children/adolescents (73.2% with migraine and 26.8% with tension-type headache) were included. We found that migraine equivalents could equally involve children with either migraine or tension-type headache and that high frequency of headache attacks correlated with migraine equivalents presence. It was concluded that migraine equivalents should not be considered merely as headache precursors, but they are part of the migrainous syndrome. In a more recent study, we showed that anxiety and somatization levels were higher in migraine children with migraine equivalents, as compared to those without migraine equivalents[2]. Our findings, together with those issued from the literature, suggest that in children and adolescents migraine equivalents should be considered as symptoms of the migrainous disease, thus their inclusion among the diagnostic criteria for pediatric migraine/tension-type headache would be hopeful.

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease which commonly shows a remitting-relapsing course. Monitoring disease activity and adaptation of immune-suppressive therapy is still a challenge in clinical practice. In previous work our group has shown that members of the S100-protein family are reliable biomarkers for monitoring arthritis in JIA patients on medication and that these proteins may even predict risk of relapses in these patients. In my talk I will present novel data regarding the local release mechanism of these proteins during joint inflammation, use of serum concentrations of these S100-proteins for monitoring JIA as well as novel molecular imaging methods based on local S100-protein expression in preclinical models of inflammation and arthritis.

JDM is the commonest inflammatory myopathy of childhood and has a wide variation in disease severity and disease course. Collaborative work has moved forward the understanding and the management of JDM in the last 10-15 years.

Anterior uveitis is a well-known threatening comorbid condition of JIA and affects around 10 to 20 % of the patients depending on JIA subtype. A large proportion of children with JIA develop uveitis in the first year of disease and 73 to 90% do so after four years of the arthritis onset. Uveitis can progress into the adulthood and usually occur as “white uveitis” which is not associated with symptoms like redness and pain as opposed to JIA related to the enthesitis subtype that is symptomatic. Factors associated to lower uveitis remission rate are: JIA diagnosis, findings of 1+ or more vitreous cells at presentation and initial visual acuity of 20/200 or worse. The Standardization of Uveitis Nomenclature (SUN) Group took the first step to define outcome measures for uveitis, but it was established just for adults. The Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC) proposed outcome measures for JIA associated uveitis incorporating the Standardization of Uveitis Nomenclature (SUN) criteria in 2011.

Juvenile idiopathic arthritis (JIA) is not a disease, but an exclusion diagnosis that encompasses all forms of arthritis that begin before the age of 16 years, persist for more than 6 weeks, and are of unknown origin. This heterogeneous group of chronic arthritides has been classified on clinical and laboratory grounds to try to identify homogeneous, mutually exclusives categories suitable for etiopathogenic studies. During the last years evidence has accumulated suggesting that while some JIA categories identify quite definite disease entities, others represent heterogeneous conditions and in particular that a homogeneous disease entity (ANA positive, early onset oligoarthritis) is included in several different JIA categories. These and other findings suggest the need to reconsider some aspects of the current International League of Associations for Rheumatology (ILAR) JIA classification and nomenclature.

Systemic juvenile idiopathic arthritis (JIA) is the most severe category within the group of arthritis which are classified under the umbrella term of JIA. Systemic JIA has been considered a therapeutic orphan until few years ago when the disease was treated primarily with corticosteroids with the known side effect especially on child growth. More recently the availability of new treatment modalities with biologic agents such as anti L6 and anti IL1 therapies have greatly advanced the possibilities for these children to be adequately treated. This lecture will describe the current status of the treatment for systemic JIA and the future perspectives.

Both MSUS and MR imaging are two suitable methods used in the investigation of immature skeleton of paediatric patients. It is important to keep in mind that these methods are complementary instead of exclusive, acting in a synergistic way when are properly combined. MSUS is a bedside method for evaluating children at all ages because of anaesthesiological support is not needed. From a paediatric rheumatologic perspective, the principal indication of MSUS is direct visualization of synovitis in peripheral joints and tendon sheaths in few minutes, even when clinical examination does not evidence abnormalities. But, MSUS imaging should never replace or precede clinical evaluation. An additional advantage of MSUS over MRI is its easy repeatability and capability to evaluate a large number of joints during a single session. The latter is of paramount importance for current ILAR classification of JIA based on the number of affected joints and the presence of particular extra-articular manifestations. Unlike MRI, MSUS is unable to display the temporomandibular joint properly. So, far, much of the ongoing development in paediatric MSUS field has been driven by a search for solutions to clinical problems. MSUSis usually used for a child with articular pain, swelling, or mechanical symptoms, without definitive diagnosis on clinical examination, in order to elucidate the diagnosis at peripheral joints. MSUS is also used to guide needle injection. Table 1 lists the main detectable musculoskeletal diseases by ultrasound in daily practice. Currently the principal applications for using MSUS in patients with JIA include: detection of synovitis, tenosynovitis, enthesitis and cartilage and bone abnormalities. To date, the role of MSUS in therapy monitoring has not been fully established. The challenge to assess synovitis has been minimized thank to technology for MSUS equipments has evolved considerably. Nevertheless, real time (or dynamic) examination is the most reliable method to distinguish quick and early between synovitis and joint cartilage leading to immediate improvement of the diagnosis and initial therapy decision of articular disorders. The MSUS appearance of tenosynovitis and enthesitis on B-mode is the same in all patients with inflammatory disease irrespective of age. As the ossification centre could show a smooth surface or irregular surface, the presence of other pathologic features along with erosion avoids misdiagnosis. MRI has proven earlier detection of bone abnormalities than MSUS. To date, the role of Doppler technique has not been entirely establishedyet. Future topics for study include: establishing international definitions for joint components in healthy children and for MSUS findings in JIA patients, consensus on scanning protocols and scoring systems, evaluation of the role of MSUS with power Doppler in the assessment of the real state of disease (activity /remission) and developing a specific training programme for paediatric rheumatologists performing US in patients with JIA.

Autoinflammatory diseases are characterized by more or less spontaneous inflammation without inciting infection or autoimmunity. These can be either acquired or genetically determined. The latter –hereditary– autoinflammatory syndromes have been classified by some as primary immunodeficiencies: defects affecting the control of the innate arm of the immune system. Immunodeficiency syndromes, however, have generally been considered to be defects in host defense, rendering the patient susceptible to infectious diseases. Even when regarding immunodeficiency and autoinflammation as separate entities, situations do occur where patients suffer both non-specific sterile inflammation and increased susceptibility to infection. This may occur in prototypic autoinflammatory diseases as well as in well recognized primary immunodeficiencies. In addition, there are intermediate disorders that are both autoinflammatory and immunodeficient by nature (table ​(table11). Table 1 Diagnosis of infection in autoinflammatory diseases is challenging, as these occur against a background of recurrent fever episodes. Conversely, ruling out infection is a prerequisite for diagnosing autoinflammation in immunodeficiency. This distinction is relevant for patient management, since some autoinflammatory patients may benefit from antimicrobial prophylaxis, whereas sterile inflammation in immunodeficiency may benefit from approaches such as interleukin-1 blockade.

The management of symptoms potentially related to hypermobility frequently require a Biopsychosocial model of management. This intervention may be provided by a variety of professionals depending upon the individual service provision; however the principals encourage an approach that promotes independent self-management. It is becoming increasingly understood that the degree of flexibility is not as important in predicting symptoms and outcomes as the degree of muscle strength and stamina as well as psychosocial factors such as levels of anxiety and low mood. It is not clear how many children with hypermobility are affected by symptoms, however musculoskeletal pain is common in young people. The principals of the physical treatments should be based around ensuring correct biomechanics are maintained with individual strengthening programmes which are then supported by paced integration into sport and physical activity. Fulltime School should be the goal for all young people with hypermobility as well as inclusion into most activities. The use of aids and adaptations including wheelchairs and crutches should be avoided as this actually promotes muscle weakness and a long term increase in symptoms. It is important that a good sleeping pattern should be restored and then maintained and the use of Active Relaxation Techniques are very effective. Teaching the young person and their family about pain and its non-pharmaceutical management is very helpful in empowering them to manage independently and not to fear pain but to be in control and therefore not limited by it. Hypermobility should be a condition that is self-managed by the young person and their family but the professionals are extremely important in ensuring this approach is understood and effective and it is their responsibility to ensure unnecessary drugs, surgeries or treatments are given to each child. The majority of young people with symptoms related to their hypermobility respond extremely well with this approach.

A group of clinical conditions with the spectrum of adult onset Spondyloarthritis (SpA) characterized at presentation by the inflammatory involvement of the lower limb joints and entheses and in some cases, particularly those with HLA-B27, sacroiliac and spinal joint involvement. Enthesitis Related Arthritis (ERA) and Psoriatic Arthritis (PsA), both categories of Juvenile Idiopathic Arthritis correspond to juvenile-onset SpA at some extentWith the advent of new classification criteria for axial SpA (axSpA) and peripheral SpA (pSpA) proposed by the Assessment of SpondyloArthritis internationalSociety (ASAS) to identify patients with ankylosing spondylitis in the earliest pre-radiographic stage of the disease to treat them with Tumor Necrosis Factor (TNF) alpha blockers and halter disease progression, there is a tendency to search for early sacroiliac involvement with Magnetic Resonance Imaging (MRI) and peripheral disease with Ultrasonographic (US) studies in childrenThere is clearly a risk in trying to resemble the objective and procedures developed for the adult patients in the pediatric population. In the first place, the most frequent and often severe inflammatory and structural changes in children and adolescents with SpA occur at peripheral sites five to 10 years before the onset of axial disease. Peripheral involvement might be so severe that TNF blockers may be indicated years before sacroiliitis and spondylitis. It is therefore obvious that searching for axial disease with MRI may be useless.Both anatomy and biomechanics of peripheral sites and axial skeleton change throughout childhood and adolescence. In consequence, it is important to understand basic aspects of the sacroiliac and spinal joints before developing plans to search such sites to detect inflammation and prescribe TNF blockers.