Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year's different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches

Drugs targeting nitric oxide synthase for migraine treatment

Introduction: Ample evidence that nitric oxide (NO) is a causative molecule in migraine has encouraged research to develop drugs that target the NO-cGMP cascade for migraine treatment. NO synthase (NOS) inhibition is an innovative therapeutic principle. Areas covered: This paper reviews the rationale underlying NOS inhibition in migraine treatment. It also provides a review on the efficacy and safety data for NOS inhibitors (nonselective NOS inhibitor L-N G -methyl-arginine hydrochloride [L-NMMA], selective inducible NOS [iNOS] inhibitors GW273629 and GW274150, combined neuronal NOS [nNOS] inhibitor and 5-HT 1B/1D receptor agonist NXN-188) in acute or preventive migraine treatment. Expert opinion: The data highlighted herein, from four placebo-controlled trials and 1 open-labeled clinical trial using 4 different NOS inhibitors on a total of 705 patients, provide convincing efficacy data only for the nonselective NOS inhibitor L-NMMA. Unfortunately, this NOS inhibitor raises cardiovascular safety concerns and has an unfavorable pharmacokinetic profile. As experimental studies predicted, iNOS inhibitors are ineffective in migraine. Still, upcoming selective nNOS inhibitors are a hope for migraine treatment, with the nNOS isoform being most clearly involved in trigeminovascular transmission and central sensitization. Future studies should help to clarify whether NOS inhibition is equally fruitful in acute and preventive treatment. It should also clarify if nNOS inhibition holds promise as a therapeutic tool for the treatment of chronic migraine and other forms of headache

Cerebral transverse sinus morphology as detected by MR venography in patients with chronic migraine.

To clarify the frequency and characteristics of altered transverse sinus morphology in a series of consecutive patients with chronic migraine. As terminology, neuroradiological techniques and patient selection differ widely across various studies, reliable, reproducible information is lacking on the frequency of cerebral transverse sinus asymmetry as measured by cerebral magnetic resonance venography in patients with chronic migraine. We assessed the frequency and characteristics of transverse sinus asymmetries and their correlation with the chronic migraine phenotype in a blind, cross-sectional magnetic resonance venographic study in a series of 83 consecutive patients with chronic migraine. After excluding mild (≤ 10%) physiological differences in transverse sinus diameter, we found magnetic resonance venographic evidence of altered transverse sinus morphology in 50.6% of the patients: 16.9% had moderate transverse sinus asymmetry (≤ 50%), 24.1% severe asymmetry (>50%), and 9.6% aplasia. Among the tested risk factors for migraine chronification, analgesic consumption, anxiety, and high systolic blood pressure were more frequent in patients with transverse sinus aplasia than in those without. Advanced magnetic resonance venographic techniques used in strictly selected subjects disclose transverse sinus asymmetries in as many as 50.6% of patients with chronic migraine, even when mild differences in physiological caliber are excluded. The unexpected correlation between transverse sinus aplasia and some risk factors for migraine chronification requires confirmation in larger studies. © 2012 American Headache Society

The first report of the Italian Migraine Registry (I-GRAINE)

Italian Migraine Registry (I-GRAINE) is a multicenter (n = 38), prospective, observational, non-interventional study aimed at providing big data on migraine to ensure proper clinical disease management, according to scientific, and sustainability criteria. We enrolled consecutive patients affected by episodic or chronic migraine according to the systematic random method. Information on sociodemographic characteristics, lifestyle, migraine features, patient's journey, and healthcare resource use were gathered using face-to-face interviews.On the date of 31 December 2021, we enrolled 231 patients at 12 headache centers. Most of them were women (84.4%), with high migraine frequency (9.6 ± 6.9 days/month) and severe disability (MIDAS score: 43.0 ± 40.8; HIT-6 score: 60.4 ± 10.6). Only a minority of patients (38.1%) had previously visited a headache center.A clear-cut difference emerged in the proportion of responders to nonspecific acute treatments (43.5-66.7%) compared to triptans (76.3%) and in responders to unspecific prophylaxis (5.4-35%) compared to anti-CGRP monoclonal antibodies (69.2-78.6%). Most patients underwent ≥ 1 specialist visit (66.9%) or diagnostic investigation (77.4%) over the last 3 years-mostly subsidized by our national health system-inappropriate in 64.9% and 25% of the cases, respectively.The I-GRAINE registry is expected to provide a large and exponentially increasing collection of clinical, biological, and epidemiologic information and will contribute to moving migraine out of the shadow cone of marginalization, which has been often relegated up to now

Natural evolution from idiopathic photosensitive occipital lobe epilepsy to idiopathic generalized epilepsy in an untreated young patient

Idiopathic photosensitive occipital lobe epilepsy (IPOE) is an idiopathic localization-related epilepsy characterized by age-related onset, specific mode of precipitation, occipital photic-induced seizures frequently consisting of visual symptoms and good prognosis. This uncommon epilepsy, which usually starts in childhood or adolescence, has rarely been observed in families in which idiopathic generalized epilepsy also affects other members. We describe a nuclear family in which the proband showed electro-clinical features of idiopathic photosensitive occipital lobe epilepsy in childhood, which subsequently evolved into absences and a single generalized tonico-clonic seizure in early adolescence. His mother had features suggestive of juvenile myoclonic epilepsy. This case illustrates a continuum between focal and generalized entities in the spectrum of the so-called idiopathic (genetically determined) epileptic syndromes. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved

Clinical experience with levetiracetam in idiopathic generalized epilepsy according to different syndrome subtypes

Clinical experience in open-label studies and anectodal reports suggest that levetiracetam is effective in generalized epilepsy. In this open-label prospective study, 19 patients (3 men, 16 women) affected by idiopathic generalized epilepsy were followed for at least 6 months following the introduction of levetiracetam. Patients were categorized according to syndrome subtype: juvenile myoclonic epilepsy (8), juvenile absence epilepsy (5), childhood absence epilepsy (4), and eyelid myoclonia with absences (2). Eleven patients received levetiracetam as monotherapy, eight as add-on therapy. Effectiveness was demonstrated in 18 patients: 13 became seizure-free (five juvenile myoclonic epilepsy, five juvenile absence epilepsy, three childhood absence epilepsy), and five achieved significant reductions in seizure frequency (three juvenile myoclonic epilepsy, one childhood absence epilepsy, one eyelid myoclonia with absences). Only one patient experienced no change in seizure frequency (eyelid myoclonia with absences). Clinical improvement was accompanied by EEG abnormality suppression or reduction. Levetiracetam was well tolerated; no patient reported side-effects

Suggestive linkage of familial mesial temporal lobe epilepsy to chromosome 3q26

Purpose: To describe the clinical findings in a family with a benign form of mesial temporal lobe epilepsy and to identify the causative genetic factors. Methods: All participants were personally interviewed and underwent neurologic examination. The affected subjects underwent EEG and most of them neuroradiological examinations (MRI). All family members were genotyped with the HumanCytoSNP-12 v1.0 beadchip and linkage analysis was performed with Merlin and Simwalk2 programs. Exome sequencing was performed on HiSeq2000, after exome capture with SureSelect 50Mb kit v2.0. Results: The family had 6 members with temporal lobe epilepsy. Age at seizure onset ranged from 8 to 13 years. Five patients had epigastric auras often associated to oro-alimentary automatic activity, 3 patients presented loss of contact, and 2 experienced secondary generalizations. Febrile seizures occurred in 2 family members, 1 of whom also had temporal lobe epilepsy. EEG showed focal slow waves and epileptic abnormalities on temporal regions in 1 patient and was normal in the other affected individuals. MRI was normal in all temporal lobe epilepsy patients. We performed single nucleotide polymorphism-array linkage analysis of the family and found suggestive evidence of linkage (LOD score = 2.106) to a region on chromosome 3q26. Haplotype reconstruction supported the linkage data and showed that the majority of unaffected family members carried the haplotype at risk. Whole exome sequencing failed to identify pathogenic mutations in genes of the candidate region. Conclusions: Our data suggest the existence of a novel locus for benign familial mesial temporal lobe epilepsy on chromosome 3q26. Our failure to identify pathogenic mutations in genes of this region may be due to limitations of the exome sequencing technology. (C) 2013 Elsevier B.V. All rights reserved

Video-EEG study of psychogenic nonepileptic seizures: Differential characteristics in patients with and without epilepsy

Purpose: Psychogenic nonepileptic seizures (PNES) are episodes that may resemble epileptic seizures (ES) but are not associated with abnormal electrical discharges in the brain. Video-EEG recording of a typical episode is considered the best diagnostic tool available. PNES are, however, also documented in patients with epilepsy (PNES/ES). The purpose of this study was to assess this comorbid population, focusing on the differences between patients with PNES/ES and patients with PNES alone. Methods: We reviewed 110 PNES episodes, occurring spontaneously or induced by means of suggestion techniques, recorded in our video-EEG laboratory over a period of eight years. We identified two subgroups of patients, consisting of 85 PNES cases and 25 PNES/ES cases, and assessed any differences in their characteristics by reviewing a number of variables (age, sex, clinical features, antiepileptic therapy, age of onset, time to diagnosis, pathological history, and length of follow-up). Results: The comparison between the two subgroups revealed that PNES/ES patients displayed some statistically significant differences when compared with PNES alone patients, i.e., younger age, a higher percentage of spontaneously activated events, a shorter disease duration, a longer time to PNES diagnosis, and a lower percentage lost at follow-up. Conclusions: This study confirms that PNES is a common, though probably underestimated, occurrence in epilepsy services. Our results shed light on some different characteristics between PNES and PNES/ES patients. © 2006 International League Against Epilepsy