New players in the preventive treatment of migraine.

Migraine is a common, chronic disorder of the brain causing much disability, as well as personal, familial and societal impact. Several oral preventive agents are available in different countries for the prevention of migraine, but none have performed better than 50% improvement in 50% of patients in a clinical trial. Additionally, each has various possible adverse events making their tolerability less than optimal. Recently, three monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) ligand (LY2951742, ALD403 and TEV-48125) and one targeting the CGRP receptor (AMG 334) have completed phase 2 trials, and the results have been reported. These early results show them all to be somewhat more effective than placebo, with no serious adverse events. Three have been studied for episodic migraine, and only TEV-48125 has been studied for both high frequency episodic and chronic migraine. Moreover, preliminary data suggests that neurostimulation is effective in migraine treatment, including stimulation of the sphenopalatine ganglion, transcutaneous supraorbital and supratrochlear nerve, and transcutaneous vagus nerve. In this article, these innovative therapies will be reviewed

Aging, cellular senescence, and progressive Multiple Sclerosis

Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression

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

Pitfals in recognition and management of trigeminal neuralgia

BACKGROUND: Trigeminal neuralgia (TN) is a severe, disabling form of painful cranial neuropathy. Even though TN has a typical clinical picture, diagnosis it is often missed or delayed in clinical practice. In order to investigate the occurrence of diagnostic and therapeutic errors in TN, we studied 102 patients suffering from TN recruited through a multicentric survey. METHODS: We performed a Pubmed database search on errors and pittfalls in TN diagnosis and management. Then, patients with TN were consecutively enrolled in the period from February 2017 to October 2019, by several European Headache Centers participating in the study, following a call of the Headache and Pain Scientific Panels of the European Academy of Neurology (EAN). Diagnosis of Classical Trigeminal Neuralgia (CTN) was made according to the International Headache Society (IHS) criteria (Tölle et al., Pain Pract 6:153-160, 2006). All the patients were evaluated using telephone/frontal interviews conducted by headache/pain specialists using an ad hoc questionnaire. RESULTS: A number of 102 patients were recruited, mostly females (F:M ratio 2.64:1). Eighty-six percent of the patients consulted a physician at the time they experienced the first pain attacks. Specialists consulted before TN diagnosis were: primary care physicians (PCP) (43.1%), dentists (in 30.4%), otorhinolaryngologists (3.9%), neurosurgeons (3.9%), neurologists or headache specialists (14.7%), others (8%). The final diagnosis was made mainly by a neurologist or headache specialist (85.3%), and the mean interval between the disease onset and the diagnosis made by a specialist was 10.8 ± 21.2 months. The "diagnostic delay" was 7.2 ± 12.5 months, and misdiagnoses at first consultation were found in 42.1% of cases. Instrumental and laboratory investigations were carried out in 93.1% of the patients before the final diagnosis of TN. CONCLUSION: While TN has typical features and it is well defined by the available international diagnostic criteria, it is still frequently misdiagnosed and mistreated. There is a need to improve the neurological knowledge in order to promptly recognize the clinical picture of TN and properly adhere to the specific guidelines. This may result in a favorable outcome for patients, whose quality of life is usually severely impaired

Safety, tolerability, and nocebo phenomena during transcranial magnetic stimulation: a systematic review and meta‐analysis of placebo‐controlled clinical trials

Background The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta‐analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied. Methods After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups. Results Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%‐3.2%) and 2.7% (95% CI 2.0%‐3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%‐22.6%) and 13.6% (95% CI 11.6%‐15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75‐3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness. Secondary meta‐analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14‐7.40) and 2.93 times higher (95% CI 1.41‐6.07), respectively, in the active treatment groups compared to placebo. Conclusions TMS is a safe and well‐tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice

Male and female sex hormones in primary headaches

Background: The three primary headaches, tension-type headache, migraine and cluster headache, occur in both genders, but all seem to have a sex-specific prevalence. These gender differences suggest that both male and female sex hormones could have an influence on the course of primary headaches. This review aims to summarise the most relevant and recent literature on this topic. Methods: Two independent reviewers searched PUBMED in a systematic manner. Search strings were composed using the terms LH, FSH, progesteron, estrogen, DHEA, prolactin, testosterone, androgen, headach, migrain, "tension type" or cluster. A timeframe was set limiting the search to articles published in the last 20 years, after January 1st 1997. Results: Migraine tends to follow a classic temporal pattern throughout a woman's life corresponding to the fluctuation of estrogen in the different reproductive stages. The estrogen withdrawal hypothesis forms the basis for most of the assumptions made on this behalf. The role of other hormones as well as the importance of sex hormones in other primary headaches is far less studied. Conclusion: The available literature mainly covers the role of sex hormones in migraine in women. Detailed studies especially in the elderly of both sexes and in cluster headache and tension-type headache are warranted to fully elucidate the role of these hormones in all primary headaches

Triptans attenuate capsaicin-induced CREB phosphorylation within the trigeminal nucleus caudalis: a mechanism to prevent central sensitization?

The c-AMP-responsive element binding protein (CREB) and its phosphorylated product (P-CREB) are nuclear proteins expressed after stimulation of pain-producing areas of the spinal cord. There is evidence indicating that central sensitization within dorsal horn neurons is dependent on P-CREB transcriptional regulation. The objectives of the study were to investigate the expression of P-CREB in cells in rat trigeminal nucleus caudalis after noxious stimulation and to determine whether pre-treatment with specific anti-migraine agents modulate this expression. CREB and P-CREB labelling was investigated within the trigeminal caudalis by immunohistochemistry after capsaicin stimulation. Subsequently, the effect of i.v. pre-treatment with either sumatriptan (n = 5), or naratriptan (n = 7) on P-CREB expression was studied. Five animals pre-treated with i.v. normal saline were served as controls. CREB and P-CREB labelling was robust in all animal groups within Sp5C. Both naratriptan and sumatriptan decreased P-CREB expression (p = 0.0003 and 0.0013) within the Sp5C. Triptans attenuate activation of CREB within the central parts of the trigeminal system, thereby leading to potential inhibition of central sensitization. P-CREB may serve as a new marker for post-synaptic neuronal activation within Sp5C in animal models relevant to migraine

Therapeutic Management: When and What

Migraine is a widespread brain disease that is classified as the second most disabling condition and has the third highest prevalence of all medical conditions. Despite its non-emergent or life-threatening nature, migraine can progress to chronic type, a subform associated with significant morbidity and drug overuse. In the management of migraine, it is important therefore to introduce early prophylactic treatment in order to limit migraine chronification. In this chapter, we will go through all the treatment options, both acute and preventive, pharmaceutical and non-pharmaceutical following this flowchart: 1. Introduction; 2. General principles; 2.1 Symptomatic therapy; 2.2 Prophylactic management; 3. Pharmaceutical therapies; 3.1 Symptomatic; 3.1.1 Disease-specific; 3.1.2 No disease-specific; 3.2 Prophylactic; 3.2.1 Disease-specific; 3.2.2 No disease-specific; 3.3 Non-Pharmaceutical therapies; 3.4 Neuromodulation; 3.4.1 Invasive; 3.4.5 Non-invasive; 3.5 Nutrient (nutraceuticals); 3.6 Dietary interventions; 3.7 Acupuncture; 3.8 Physical therapy; 4. Cognitive behavioral therapies; 5. Patient centricity and patient education