OnabotulinumtoxinA in elderly patients with chronic migraine: insights from a real-life European multicenter study.

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients. METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs). RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients. CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

Establishment of an Italian chronic migraine database: a multicenter pilot study.

To optimize chronic migraine (CM) ascertainment and phenotype definition, provide adequate clinical management and health care procedures, and rationalize economic resources allocation, we performed an exploratory multicenter pilot study aimed at establishing a CM database, the first step for developing a future Italian CM registry. We enrolled 63 consecutive CM patients in four tertiary headache centers screened with face-to-face interviews using an ad hoc dedicated semi-structured questionnaire gathering detailed information on life-style, behavioral and socio-demographic factors, comorbidities, and migraine features before and after chronicization and healthcare resource use. Our pilot study provided useful insights revealing that CM patients (1) presented in most cases symptoms of peripheral trigeminal sensitization, a relatively unexpected feature which could be useful to unravel different CM endophenotypes and to predict trigeminal-targeted treatments' responsiveness; (2) had been frequently admitted to emergency departments; (3) had undergone, sometime repeatedly, unnecessary or inappropriate investigations; (4) got rarely illness benefit exemption or disability allowance only. We deem that the expansion of the database-shortly including many other Italian headache centers-will contribute to more precisely outline CM endophenotypes, hence improving management, treatment, and economic resource allocation, ultimately reducing CM burden on both patients and health system.

Quality indicators in headache care: an implementation study in six Italian specialist-care centres.

BACKGROUND: Headache disorders are highly prevalent, and have a substantial and negative impact on health worldwide. They are largely treatable, but differences in structure, objectives, organization and delivery affect the quality of headache care. In order to recognize and remedy deficiencies in care, the Global Campaign against Headache, in collaboration with the European Headache Federation, recently developed a set of quality indicators for headache services. These require further assessment to demonstrate fitness for purpose. This is their first implementation to evaluate quality in headache care as a multicentre national study. METHODS: Between September and December 2016, we applied the quality indicators in six Italian specialist headache centres (Bologna, Firenze, Modena, Padova, Roma Campus Bio-Medico and Roma Sapienza). We used five previously developed assessment instruments, translated into Italian according to Lifting The Burden's translation protocol for hybrid documents. We took data from 360 consecutive patients (60 per centre) by questionnaire and from their medical records, and by different questionnaires from their health-care providers (HCPs), including physicians, nurses, psychologists and nursing assistants. RESULTS: The findings, comparable between centres, confirmed the feasibility and practicability of using the quality indicators in Italian specialist headache centres. The questionnaires were easily understood by HCPs and patients, and were not unduly time-consuming. Diagnoses were almost all (> 97%) according to ICHD criteria, and routinely (100%) reviewed during follow-up. Diagnostic diaries were regularly used by 96% of physicians. Referral pathways from primary to specialist care existed in five of the six clinics, as did urgent referral pathways. Instruments to assess disability and quality of life were not used regularly, a deficiency that needs to be addressed. CONCLUSION: This Italy-wide survey confirmed in six specialist centres that the headache service quality indicators are fit for purpose. By establishing majority practice, identifying commonalities and detecting deficits as a guide to quality improvement, the quality indicators may be used to set benchmarks for quality assessment. The next step is extend use and evaluation of the indicators into non-specialist care.

Headache in epilepsy: prevalence and clinical features.

BACKGROUND: Headache and epilepsy are two relatively common neurological disorders and their relationship is still a matter of debate. Our aim was to estimate the prevalence and clinical features of inter-ictal (inter-IH) and peri-ictal headache (peri-IH) in patients with epilepsy. METHODS: All patients aged ≥ 17 years referring to our tertiary Epilepsy Centre were consecutively recruited from March to May 2011 and from March to July 2012. They underwent a semi-structured interview including the International Classification Headache Disorders (ICHD-II) criteria to diagnose the lifetime occurrence of headache.χ(2)-test, t-test and Mann-Whitney test were used to compare clinical variables in patients with and without inter-IH and peri-IH. RESULTS: Out of 388 enrolled patients 48.5 % had inter-IH: migraine in 26.3 %, tension-type headache (TTH) in 19.1 %, other primary headaches in 3.1 %. Peri-IH was observed in 23.7 %: pre-ictally in 6.7 %, ictally in 0.8 % and post-ictally in 19.1 %. Comparing patients with inter-ictal migraine (102), inter-ictal TTH (74) and without inter-IH (200), we found that pre-ictal headache (pre-IH) was significantly represented only in migraineurs (OR 3.54, 95 % CI 1.88-6.66, P < 0.001). Post-ictal headache (post-IH) was significantly associated with both migraineurs (OR 2.60, 95 % CI 1.85-3.64, P < 0.001) and TTH patients (OR 2.05, 95 % CI 1.41-2.98, P < 0.001). Moreover, post-IH was significantly associated with antiepileptic polytherapy (P < 0.001), high seizure frequency (P = 0.002) and tonic-clonic seizures (P = 0.043). CONCLUSIONS: Migraine was the most represented type of headache in patients with epilepsy. Migraineurs are more prone to develop pre-IH, while patients with any inter-IH (migraine or TTH) are predisposed to manifest a post-IH after seizures.

Biochemistry of primary headaches: role of tyrosine and tryptophan metabolism.

The pathogenesis of migraine as well as cluster headache (CH) is yet a debated question. In this review, we discuss the possible role of the of tyrosine and tryptophan metabolism in the pathogenesis of these primary headaches. These include the abnormalities in the synthesis of neurotransmitters: high level of DA, low level of NE and very elevated levels of octopamine and synephrine (neuromodulators) in plasma of episodic migraine without aura and CH patients. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward an increased decarboxylase and reduced hydroxylase enzyme activities. The metabolic shift of the tyrosine is favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity present in migraine. In addition we present biochemical studies performed in chronic migraine and chronic tension-type headache patients to verify if the same anomalies of the tyrosine and tryptophan metabolism are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine metabolism are present only in CM patients (very high plasma levels of DA, NE and tryptamine). Tryptamine plasma levels were found significantly lower in both CM and CTTH patients. In view of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold.

Headache in school age.

Headache, especially migraine and tension-type headache, is one of the most frequently reported somatic complaints by children and adolescents. Different population-based studies have been conducted to study the correlation between headache and lifestyles in pediatric age, nevertheless, the obtained results are often controversial and these relationship still remain unclear. Likewise, is still strongly debated the burden of headache during school age, its impact on school performances and on quality of life of children and their families. Consequently, larger studies are necessary to evaluate the degree of disability due to pediatric headache. We summarize the ongoing knowledge about these concepts, with the intent to provide useful data to neurologists but also to primary care providers, to further improve the management of pediatric headaches by preventing the headache progression, the disabling effects associated and improving the long-term outcome.

Herbal therapy in migraine.

The use of herbal therapies is ancient and increasing worldwide. There is a growing body of evidence supporting the efficacy of various "complementary" and alternative medicine approaches in the management of headache disorders. Promising tools to treat migraine patients are herbal products. In particular constituents of Petasites hybridus, Tanacetum Parthenium and Ginkgo Biloba have shown antimigraine action in clinical studies. A miscellaneous of recreational drugs and other herbal remedies have been supposed to have a role in headache treatment but quality of clinical studies in this field is low and inconclusive. Further research is warranted in this area.

Nociception and autonomic nervous system.

The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain may also be experienced in absence of noxious stimuli and together with temperature and other bodily feelings constitute the interoception redefined as the sense of the physiological condition of the entire body, not just the viscera. The main characteristic of these feelings is the affective aspect. Emotion, motivation, and consequent behavior connected with these feelings characterize their homeostatic role. This implies an interaction between neural structures involved in pain sensation and autonomic control. The aim of this review is to focus on pain perception, mainly on pain matrix structures' connections with the autonomic nervous system.

Controversies in migraine treatment: opioids should be avoided.

The use of opioids for migraine is still controversial. Evidence-based guidelines do not recommend opioids as first-line treatment of migraine attacks, while clinical and epidemiological surveys demonstrate that the use of opioids is associated with more severe headache-related disability, symptomology and comorbidities, and greater health-care resource utilization. There are concerns that opioids may be misused or abused, leading to opioid abuse or dependence and migraineurs are particularly prone and at risk for the development of chronic daily headache from opioids overuse. Since clinical and preclinical studies evidence a pathophysiological role of opioids in migraine progression, opioids should be avoided in migraine patients.

Migraine and sleep disorders.

The burden of migraine strongly increases, considering its linkage with sleep disorders. Migraine is positively associated with many sleep-complaint disorders; some are confirmed by several studies, such as restless leg syndrome, whereas others still remain uncertain or controversial, e.g. narcolepsy. Many studies have investigated the association between headache and other sleep disturbances such as daytime sleepiness, insomnia, snoring and/or apnea, but only a few have focused on migraine. Highlighting the comorbidity between migraine and sleep disorders is important to improve treatment strategies and to extend the knowledge of migraine pathophysiology.

Migraine: risk factor and comorbidity.

The burden of migraine strongly increases considering its linkage with other psychiatric, neurological, cardiovascular and cerebrovascular diseases. Migraine is positively associated with many disorders: some are confirmed by several studies whereas others remain uncertain or controversial. The association with some disorders is not simply due to concomitance but it implies a linkage in terms of causality. Highlighting these relationships is important to improve treatment strategies, broaden our knowledge of the pathophysiology and understand if migraine is per se a modifiable risk factor for some disorders.

Migraine and cardiovascular diseases.

Migraine has complex relationships with cerebrovascular and cardiovascular disorders but also with cardiac anomalies. Patients affected by migraine with aura have an increased prevalence of right-to-left shunt due to patent foramen ovale or pulmonary arteriovenous malformations. The association between ischemic heart disease, cardiovascular mortality and migraine remains unsettled. The debate focuses on a physiopathological link between migraine and cardiovascular diseases or a higher prevalence of risk factors in migraineurs.

SPARTACUS: underdiagnosis of chronic daily headache in primary care.

Despite the burden of chronic daily headache (CDH), general practitioners' (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs' knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

Italian Law "measures to guarantee the access to palliative and pain treatments": rebound on headaches' management.

The Italian Law 38/2010 assures the citizens' right to have access to palliative care and to antalgic centres in case of either oncologic or non-oncologic pain. It represents an opportunity for headaches' managements in Italy, promoting the creation of regional and national networks of headache centres and local diagnostic and therapeutic clinical pathways for patient affected with headache. This law should also support collaborations between both antalgic and headache centres networks in order to promote innovative or experimental procedures for chronic and refractory headaches. Moreover, art. 10 of the Law 38/2010 may facilitate the prescription of many headache prophylactic drugs but it may be a risk for opioids overuse headache. Educational programs and the Continuous Professional Development for physicians and all different healthcare professionals in headache area are warranted.

Spectral analysis of heart rate variability reveals an enhanced sympathetic activity in narcolepsy with cataplexy.

OBJECTIVE: To test the autonomic control of cardiovascular reflexes and heart rate variability (HRV) at rest and during orthostatic stress in narcolepsy with cataplexy (NC). METHODS: Ten NC patients with a hypocretin deficit and 18 control subjects underwent head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing and cold face under controlled laboratory conditions. Heart rate variability (HRV) was analysed during supine rest and HUTT considering the normalized unit of LF and HF power (LFnu; HFnu), using autoregressive (AR) and fast Fourier transform (FFT) algorithms. RESULTS: Cardiovascular changes during HUTT, Valsalva manoeuvre, deep breathing, isometric handgrip and cold face were normal and comparable in the two groups. AR and FFT analysis showed an increased LF/HF ratio in NC patients during supine rest. As expected, LFnu increased and HFnu decreased in the control group during HUTT, but did not change in narcoleptics being comparable to values in the supine condition. CONCLUSIONS: NC patients showed an increased sympathetic drive on heart rate (HR) in the supine condition that did not further increase during HUTT. SIGNIFICANCE: These results suggest the proper functioning of cardiovascular reflexes in NC but support an impairment of HR modulation at rest in favour of an enhanced sympathetic activity.

Clinical and neuroimaging evidence of interictal cerebellar dysfunction in FHM2.

We used multimodal magnetic resonance (MR) techniques [brain diffusion-weighted magnetic resonance imaging, diffusion-weighted imaging (DWI), proton MR spectroscopy (MRS), (1)H-MRS; and skeletal muscle phosphorous MRS, (31)P-MRS] to investigate interictal brain microstructural changes and tissue energy metabolism in four women with genetically determined familial hemiplegic migraine type 2 (FHM2), belonging to two unrelated families, compared with 10 healthy women. Brain DWI revealed a significant increase of the apparent diffusion coefficient median values in the vermis and cerebellar hemispheres of FHM2 patients, preceding in two subjects the onset of interictal cerebellar deficits. (31)P-MRS revealed defective energy metabolism in skeletal muscle of FHM2 patients, while brain (1)H-MRS showed a mild pathological increase in lactate in the lateral ventricles of one patient and a mild reduction of cortical N-acetyl-aspartate to creatine ratio in another one. Our MRS results showed that a multisystem energy metabolism defect in FHM2 is associated with microstructural cerebellar changes detected by DWI, even before the onset of cerebellar symptoms.

Underdiagnosis and undertreatment of migraine in Italy: a survey of patients attending for the first time 10 headache centres.

The aim of this study was to asses the clinical features, pattern of healthcare and drug utilization of migraine patients attending 10 Italian headache centres (HC). Migraine is underdiagnosed and undertreated everywhere throughout the world, despite its considerable burden. Migraine sufferers often deal with their problem alone using self-prescribing drugs, whereas triptans are used by a small proportion of patients. All patients attending for the first time 10 Italian HCs over a 3-month period were screened for migraine. Migraine patients underwent a structured direct interview about previous migraine diagnosis, comorbidity, headache treatments and their side-effects and healthcare utilization for migraine. Patient satisfaction with their usual therapy for the migraine attack was evaluated with the Migraine-Assessment of Current Therapy (ACT) questionnaire. The quality of life of migraine patients was assessed by mean of Short Form (SF)-12 and Migraine-Specific Quality of life (MSQ) version 2.1 questionnaires. Of the 2675 patients who attended HCs for the first time during the study period, 71% received a diagnosis of migraine and the first 953 subjects completed the study out of 1025 patients enrolled. Only 26.8% of migraine patients had a previous diagnosis of migraine; 62.4% of them visited their general practitioner (GP) in the last year, 38.2% saw a specialist for headache, 23% attended an Emergency Department and 4.5% were admitted to hospital for migraine; 82.8% of patients used non-specific drugs for migraine attacks, whereas 17.2% used triptans and only 4.8% used a preventive migraine medication. Triptans were used by 46.4% of patients with a previous diagnosis of migraine. About 80% of migraine patients took over-the-counter medications. The Migraine-ACT revealed that 60% of patients needed a change in their treatment of migraine attacks, 85% of whom took non-specific drugs. Both the MSQ version 2.1 and the SF-12 questionnaires indicated a poor quality of life of most patients. Migraine represents the prevalent headache diagnosis in Italian HCs. Migraine is still underdiagnosed in Italy and migraine patients receive a suboptimal medical approach in our country, despite the healthcare utilization of migraine subjects being noteworthy. A cooperative network involving GPs, neurologists and headache specialists is strongly desirable in order to improve long-term migraine management in Italy.

Effect of deep brain stimulation of the posterior hypothalamic area on the cardiovascular system in chronic cluster headache patients.

The objective of this study was to determine the cardiovascular effects of chronic stimulation of the posterior hypothalamic area (PHA) in cluster headache (CH) patients. Systolic and diastolic blood pressure (SBP, DBP), cardiac output, total peripheral resistance (TPR), heart rate (HR) and breathing were monitored at supine rest and during head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing, cold face test and isometric handgrip in eight drug-resistant chronic CH patients who underwent monolateral electrode implantation in the PHA for therapeutic purposes. Autoregressive power spectral analysis (PSA) of HR variability (HRV) was calculated at rest and during HUTT. Each subject was studied before surgery (condition A) and after chronic deep brain stimulation (DBS) of PHA (condition B). Baseline SBP, DBP, HR and cardiovascular reflexes were normal and similar in both conditions. With respect to condition A, DBP, TPR and the LF/HF obtained from the PSA of HRV were significantly (P < 0.05) increased during HUTT in condition B. In conclusion, chronic DBS of the PHA in chronic CH patients is associated with an enhanced sympathoexcitatory drive on the cardiovascular system during HUTT.

Application of ICHD-II and revised diagnostic criteria to patients with chronic daily headache.

The objective of this study was to evaluate how the criteria of the second edition of the International Classification of Headache Disorders (ICHD-II) and the revised criteria fit a sample of patients with chronic daily headache (CDH). One hundred and five patients with CDH in a tertiary headache centre were included. Headache was assessed using a semi-structured interview. Patients were classified according to the ICHD-II and to the new appendix criteria of the ICHD. Using the ICHDII, 91% of patients received a combination of diagnoses and 76% received only a probable diagnosis: 47% had probable chronic migraine (CM) with probable medication overuse headache (MOH), 28% had probable chronic tension-type headache (CTTH) with probable MOH, 20% had CTTH and 3.8% had CM. Using the new appendix criteria, 88.5% of patients required one diagnosis. Seventy-six percent of patients were classified as MOH, 17% had CTTH and 6.7% had CM. The classification of CDH remains controversial. Alternative criteria for CM with and without medication overuse are discussed.