Dimos-Dimitrios Mitsikostas

Refractory chronic migraine: a Consensus Statement on clinical definition from the European Headache Federation

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).

TNFR2 on non-haematopoietic cells is required for Foxp3+ Treg-cell function and disease suppression in EAE

The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17‐cell responses and reduced numbers of Foxp3+ Treg cells both in the spinal cord and peripheral lymphoid organs. Treg cells from TNFR2‐deficient animals developing EAE show decreased proliferative and suppressive functions, both ex vivo and in vivo, and appear responsible for the exacerbated non‐remitting disease, as evidenced by phenotypic rescue following adoptive transfer of Treg cells from WT but not TNFR2−/− donors. Reciprocal BM transplantation experiments between WT and TNFR2‐deficient mice demonstrated that the capacity of TNFR2 to support Treg‐cell expansion and function during EAE is non‐intrinsic to Treg or other haematopoietic cells but requires expression of TNFR2 in radiation‐resistant cells of the host. These results reveal a previously unsuspected role for non‐haematopoietic TNFR2 in modulating Treg‐cell expansion and immune suppression during development of autoimmunity and suggest that a similar mechanism may affect chronicity and relapses characterizing human autoimmune disease, including MS.

Cluster headache: a quasi-rare disorder needing a reappraisal

This Editorial introduces the 2015 Open Thematic Series dedicated to Cluster Headache (CH) and other Rare Headaches. For too long researchers have focused their attention on other most popular, sometimes clumsy or foggy forms of headache, overlooking this important and quasi-rare headache disorder [1]. n nApparently CH represents the most peculiar form among the Trigeminal Autonomic Cephalalgias (TACs). The unbearable periorbital side-locked pain is coupled by ipsilateral cranial autonomic symptoms (conjunctival injection, lacrimation and rhinorrhea) and causes a vast disability although the overall burden of this disease has not yet found a complete systematization. n nEspecially its chronic form, characterized by more days with attacks than not in the year span, represents a strict minority (10xa0% of CH, 0,01xa0% overall) and hits 70.000 on a sample of 100 millions of people. Even if these numbers are relatively small the impact of this disease is destructive, thus CH represents a niche worth to be re-focused. n nRecently Chronic CH (CCH) refractory to whichever medical therapy (rCCH) has been systematized from a clinical point of view [2]. n nThe personal burden caused by CH, meant as loss of employment, homebound days and disability is higher in women than in men [3]. n nCH lifetime prevalence is 1/1000 and over the past decades a progressive reduction of the male/female ratio has been reported, being now 2.1:1 [4]. Even if CH is easy to diagnose on the basis of its peculiar features, the timing over the day of the attacks (up to 8), a temporally defined active cluster period (60–90 days) and its seasonal recurrence, only 1/3 of these patients is rightly diagnosed, with an unacceptable delay of 5.3xa0years and consequently more than 2/3 of them never receive a correct treatment [1, 5, 6]. n nActually the current pathophysiological theory of CH is oriented towards a posterior hypothalamic dysfunction [7] but further pharmacological studies shall selectively focus this area. Recently the allele G of the G1246A HCRTR2 polymorphism was been found to be associated with CH, indicating that hypocretin/orexin system’s peptides may be involved in the transmission of pain, in autonomic and neuroendocrine functions, and in the pathogenesis of CH [8, 9]. n nFor too many years sumatriptan, verapamil and corticosteroids have been the cornerstones of CH treatment [1]; we hope that the starting era of monoclonal antibodies against Calcitonin Gene-Related Peptide might include CH as therapeutic target. An ongoing phase 3 RCT on the use of LY2951742 in episodic CH through its preventative subcutaneous administration every 30xa0days could change the future management of CH [10]. n nOther approaches to chronic cluster headache are the new mini-invasive and non-invasive neuromodulation techniques. The European Headache Federation recommends caution in using these techniques [11] because only few controlled studies have been carried out yet. n nAmong these new approaches, Vagal Nerve Stimuation (VNS) and sphenopalatine ganglion stimulation (SPG) seem promising but still classified at Class IV evidence [12, 13]; SPG shows contrasting evidence [14]. All these approaches need to be further confirmed and validated by ad hoc RCTs. n nLastly, patients’ education is another important topic to be re-considered: sleep pattern changes, alcoholic beverages, NO-derived cardiovascular drugs and phosphodiesterase inhibitors widely self-prescribed for erectile dysfunction trigger additional bouts during CH active phases [1]. Furthermore, a more diffuse physicians education on CH management should lead to an earlier diagnosis and a more adequate treatment of this headache disorder [15]. n nThus we trust that this Open Thematic Series dedicated to Cluster Headache could thicken the attention on a famed and quasi-rare headache disorder.

Update on Medication-Overuse Headache and Its Treatment.

Opinion statementMedication-overuse headache—i.e., a too-frequent consumption of acute headache medications leading to increased headache frequency and reduced effectiveness of acute and preventive treatments—is a serious medical condition whose pathophysiology still remains incompletely known, which is reflected into a lack of mechanism-based treatments. The first mandatory step in the therapeutic strategy remains withdrawal of the abused drug, preferably abrupt, in concomitance with a detoxification pharmacological regimen to lessen withdrawal symptoms. Intravenous hydration, antiemetics, corticosteroids (prednisone), tranquilizers (benzodiazepine), neuroleptics, and rescue medication (another analgesic than the overused) should be delivered in various combinations, on an inpatient (hospitalization and day hospital) basis or outpatient basis, depending on the characteristics of the specific patient and type of overuse. Inpatient withdrawal should be preferred in barbiturate and opioid overuse, in concomitant depression, or, in general, in patients who have difficulty in stopping the overused medication as outpatients. In contrast, in overuse limited to simple analgesics in highly motivated patients, without high levels of depression and/or anxiety, home detoxification should be chosen. Re-prophylaxis should immediately follow detoxification, ideally with local injections of onabotulinumtoxinA every 3xa0months or topiramate orally for at least 3xa0months. Adequate information to patients about the risks of a too-frequent consumption of symptomatic headache medications is essential and should constantly parallel treatment to help preventing relapse after detoxification and re-prophylaxis.

Greater occipital nerve as target for refractory chronic headaches: from corticosteroid block to invasive neurostimulation and back.

Headache disorders are one of the major causes of disability worldwide, recently classified as the third cause by the Global Burden of Disease 2010 [1]. Their chronic form and refractory headaches are to be considered important challenges in the daily management of a third-level headache center. The pyramidal progression toward structures characterized by more and more complex and multidisciplinary competences is a given fact based on the research of innovative solutions and multimodal approaches. The clinical definition of the most relevant forms of chronic headaches not responding to conventional therapies is best figured in refractory chronic headaches (rCHs), more precisely refractory chronic cluster headache (rCCH) and refractory chronic migraine (rCM) complicated by acute drug overuse. The European Headache Federation (EHF) has defined the clinical concept of refractoriness in two separate consensus papers, one for rCM [2] and the other for rCCH [3]. For decades, the great occipital nerve block (GONb) through the use of corticosteroids or, more recently, the implant of a neurostimulation device has been considered a target for headaches that are difficult to treat [4–6]. Experts consider the safety of the corticosteroid an option, in the context of a multidisciplinary approach, before the final decision to perform occipital nerve stimulation (ONS) in most severely affected patients with rCCH (but not chronic migraine), although a positive response to GONb may not be assumed as predictive for the therapeutic effect of ONS [2,3]. The anatomic connection between GON and C2 roots supplied the rationale of a central action reducing or minimizing the nociceptive transmission into the trigemino-cervical complex via intracranial dural nociceptive inputs [7]. Such a mechanism has been hypothesized for GON neurostimulation through 2 kHz and for spinal cord stimulation (SCS) through 10 kHz electric impulses in both rCCH and rCM [8]: the novel use of high frequency (kHz) in SCS is because it results in a stimulation without paresthesia, usually present in ONS and traditional SCS, where frequencies generally used are in the range of 30–60 Hz [9]. Corticosteroid block as transitional therapy

Nocebo in Alzheimer's disease; meta-analysis of placebo-controlled clinical trials

BACKGROUND AND PURPOSEnNocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in Randomized Controlled Studies (RCTs) for Alzheimers Disease (AD).nnnMETHODSnAfter a systematic Medline search for RCTs for AD pharmacological treatments, we assessed the number of placebo-treated patients reporting at least one AE and the number of discontinuations because of placebo intolerance and searched for factors correlating to nocebos extent.nnnRESULTSnData were extracted from 20 RCTs fulfilling our search criteria. Of 3049 placebo-treated patients, 57.8% (95% CI: 50.1%-66.7%) reported at least one AE and 6.6% (95% CI: 5.3%-8.4%) discontinued placebo treatment because of AEs. All patients participating in these RCTs reported similar AEs independently of the study arm they belonged. Nocebo AE rate and dropout rate were positively related to study population size. The rates of AEs and dropouts because of AEs were parallel between placebo and active arms of RCTs (r=0.812, p<0.001 and r=0.787, p<0.001, respectively). Effectiveness rates correlated significantly to ΑΕs rate and dropout rate because of AEs in placebo treated patients (r=0.787, p<0.001 and r=0.812, p<0.001, respectively).nnnCONCLUSIONnIn RCTs for AD one out of fifteen patients treated with placebo dropped out because of AEs and three out of five experienced AEs indicating that adherence and effectiveness may be adversely affected with additional implications for clinical practice. The principal implications of this paper are that nocebo deserves much.

Nocebo effect in refractory partial epilepsy during pre-surgical monitoring: Systematic review and meta-analysis of placebo-controlled clinical trials

PURPOSEnNocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in Randomized Controlled Studies (RCTs) for Epilepsy.nnnMETHODnAfter a systematic Medline search for RCTs for Epilepsy pharmacological treatments, we assessed the number of discontinuations because of placebo intolerance.nnnRESULTSnData were extracted from 4 RCTs fulfilling our search criteria. Three out of 5 placebo-treated patients (60.8%) reported at least one AE and 4.0% discontinued placebo treatment because of AEs. All patients participating in the epilepsy RCTs reported similar AEs independently of the study arm they belonged.nnnCONCLUSIONnVery limited epilepsy RCTs with pure placebo groups are available and all are in treatment resistant patients during pre-surgical monitoring. However, our study indicates a significant nocebo effect in trials for epilepsy treatment adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial designing.

Headache and pregnancy: a systematic review.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify “red flag symptoms” suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

Refractory Headache: One Term does Not cover All – A Statement of the European Headache Federation

In the past years a unifying definition of refractory headache (rH) has been extensively discussed [1,2] but, to date, has not been agreed upon. It is widely agreed, that refractoriness, for whatever category and disease, implies a high burden with tremendous impact in health related quality of life (HRQoL) [3]. Despite that fact, an overall accepted definition of rH would be more than important for managing and triaging patients to an appropriate level of care and for determining eligibility for epidemiological and clinical studies. n nSo far, there are different and non-conclusive categories that try to describe refractoriness. In the understanding of refractoriness particular in headache patients several important issues have to be addressed: First, it is of importance to emphasize the difficulty that refractoriness in headache may just represent more or less treatable version(s) of many different disorders, rather than a unique disease or group of disorders. Second, the same patient might be identified as refractory at one time, but treatment responsive at another. Therefore it may be of crucial importance to evaluate acute and prophylactic treatment response, baseline headache severity, partial response versus an all-or-none response, and the possibility of any variability in the treatment response over time for each headache disorder and patient from the very first on. Some evidence supports the hypothesis that baseline headache attack intensity has an impact on determination of treatment response [4]. It may also be hypothesized that patients with high baseline headache frequency were more likely to be drug resistant, meaning that it is harder to eradicate many headache attacks than a few. Without recording baseline frequency and severity rate, it is almost impossible to know whether there has been partial or no response to treatment. But that’s the crucial point: clinicians have the need for medical treatment mostly before severity of headache and frequency of disease can be determined. When headache attacks are not completely controlled, the conclusion may be that the administered drug is not effective and that the patient therefore is “resistant”. Third, as in other conditions [5] the definition of responder or non-responder enormously differs among both clinicians and investigators. n nAll these considerations lead to variability in clinical and epidemiological research results, both being of importance to increase our knowledge in the understanding of rH. What are the critical issues so far: (i) there is no standardized definition of rH; (ii) at the time of first diagnosis headache patients do not necessarily become refractory immediately, nor do they mandatorily remain refractory throughout the course of their disease; (iii) due to the necessity that most patients should be treated rapidly after diagnosis response to medication often is assessed without a pretreatment baseline and it remains unclear whether or not so-called refractory patients have had a substantial response to treatment; (iv) headache pain and associated symptoms are frequently intermittent, making this disease different from others that have been examined for treatment resistance; (v) the natural history is not known. n nFor all these purposes the Board of the European Headache Federation (EHF) felt the need to develop new consensus criteria that define refractory chronic migraine (rCM) and refractory chronic cluster headache (rCCH). These new definitions of rCM and rCCH, which were agreed upon within the EHF, allows us to separate patients into categories of refractory and non-refractory, being important for clinicians, clinical and epidemiological trials. n nThe EHF is aware of that still many challenges are on the road in identifying which patients are really treatment resistant and to what degree. It is a misconception that a patient necessarily will fall into one of the two categories and stay there. From a clinical perspective a large number of patients may fit each category for periods of time. But patients may also move in both directions, from refractory to responsive and the opposite. E.g. after neuromodulation, many patients will become headache free but have to continue with prophylactic medication to prevent headache recurrence. These patients have shifted from being treatment resistant to being treatment sensitive. n nTo define treatment response - EHF claims the need to go into patient categorization - one term does not fit all. We badly need the same definitions of rH, better information about pretreatment headache rate and severity, more precise information about prior acute and prophylactic treatment response and scientific data regarding the natural history of drug response.

Framing education on headache disorders into the Global Burden of Disease Study 2010. The European Headache Federation stands ready

Framing education on headache disorders into the Global Burden of Disease Study 2010. The European Headache Federation stands ready.