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Sommer RJ, Robbins BT. Migraine Headache and Patent Foramen Ovale: Observational Studies, the Randomized Clinical Trials, and the GORE RELIEF Clinical Study. Cardiol Clin 2024; 42:497-507. [PMID: 39322340 DOI: 10.1016/j.ccl.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
The pathophysiology of migraine remains poorly understood. Like most migraine preventive therapies, patent foramen ovale (PFO) closure was never intended for the treatment of migraine. After closure of PFO for other reasons, migraine symptom reduction/elimination was noted in some patients. Subsequent small trials failed to prove its benefit. There is significant evidence suggesting a platelet-mediated mechanism linking migraines to PFO. The GORE RELIEF Clinical Study is a randomized, blinded, placebo- and sham-controlled trial, currently enrolling. The study design is meant to optimize patient selection using thienopyridine responsiveness as an inclusion criterion.
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Affiliation(s)
- Robert J Sommer
- Department of Medicine, Division of Interventional Cardiology, Columbia University Medical Center, 161 Fort Washington Avenue, Room 624, New York, NY 10032, USA.
| | - Barbara T Robbins
- Department of Medicine, Division of Interventional Cardiology, Columbia University Medical Center, 161 Fort Washington Avenue, Room 624, New York, NY 10032, USA
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D'Apolito M, Rispoli MG, Ajdinaj P, Travaglini D, Bonanni L. Sporadic hemiplegic migraine with novel missense mutation in the SCN1A gene and positive response to anti-CGRP antibody: a case report. Neurol Sci 2024; 45:5535-5537. [PMID: 38940877 DOI: 10.1007/s10072-024-07665-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Affiliation(s)
- Maria D'Apolito
- Department of Neuroscience and Imaging, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | | | - Paola Ajdinaj
- Department of Neuroscience and Imaging, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | | | - Laura Bonanni
- Department of Medicine and Aging Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.
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Maita H, Kobayashi T, Akimoto T, Osawa H, Hanada H. Transient hemiplegia in a patient with migraine: A case of sporadic hemiplegic migraine. SAGE Open Med Case Rep 2024; 12:2050313X241275386. [PMID: 39193233 PMCID: PMC11348355 DOI: 10.1177/2050313x241275386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 07/23/2024] [Indexed: 08/29/2024] Open
Abstract
Hemiplegic migraine is a rare form of migraine characterized by aura with unilateral paralysis; however, studies on its treatment are limited. A 39-year-old man with migraine headaches and myofascial pain syndrome was referred to our hospital with transient right hemiplegia, after presenting to an outside emergency department with headache and right hemiplegia 2 days prior. Computed tomography, magnetic resonance imaging, and blood test results revealed no abnormalities. The symptoms resolved spontaneously; he was referred to our hospital. Based on the International Classification of Headache Disorders, Third Edition criteria, he was diagnosed with sporadic hemiplegic migraine. Propranolol was added to his regular regimen as prophylactic treatment, which resulted in reduction in his migraine frequency. Over the next 2 years, no recurrent paralysis occurred. Hemiplegic migraines should be considered in patients with migraine exhibiting transient hemiplegia without obvious intracranial abnormalities. Prophylactic treatment with propranolol could be effective in treatment of hemiplegic migraine.
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Affiliation(s)
- Hiroki Maita
- Development of Community Healthcare, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Tadashi Kobayashi
- Department of General Medicine, Hirosaki University School of Medicine and Hospital, Aomori, Japan
| | - Takashi Akimoto
- Emergency Disaster and General Medicine, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Hiroshi Osawa
- Department of General Medicine, Hirosaki University School of Medicine and Hospital, Aomori, Japan
| | - Hiroyuki Hanada
- Development of Community Healthcare, Hirosaki University Graduate School of Medicine, Aomori, Japan
- Department of General Medicine, Hirosaki University School of Medicine and Hospital, Aomori, Japan
- Emergency Disaster and General Medicine, Hirosaki University Graduate School of Medicine, Aomori, Japan
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Woodham TJ, Haas JW, Fortner MO, Oakley PA, Harrison DE. Resolution of Sporadic Hemiplegic Migraine by Correcting a Cervical Spine Kyphosis Utilizing the Chiropractic BioPhysics® (CBP®) Technique: A Case Report With Long-Term Follow-Up. Cureus 2024; 16:e63774. [PMID: 38974394 PMCID: PMC11227427 DOI: 10.7759/cureus.63774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2024] [Indexed: 07/09/2024] Open
Abstract
A 19-year-old male suffered from sporadic hemiplegic migraine (SHM) for several years and experienced significant pain and disability with sensory and motor disturbances during the migraine headaches. Weakness, abnormal vision, abnormal sensation, one-sided disabling motor weakness, and other signs of SHM were diagnosed. The patient had received previous physical therapy, chiropractic and over-the-counter medications, as well as migraine-specific prescriptions without lasting improvements. Chiropractic BioPhysics® (CBP®) spinal structural rehabilitation protocols were used to increase cervical lordosis and improve cervical muscular strength, mobility, and posture. These protocols include spine-specific prescriptions for Mirror Image® postural exercises, traction, and spinal manipulative therapy. After 24 treatments over eight weeks, all subjective and objective outcomes improved dramatically with a near resolution of all initial symptoms of SHM. There were a significant increase in cervical lordosis and a reduction in forward head posture. The neck disability index improved from 26% to 6%, and all pain scores for all regions improved following treatment. A 10-month follow-up exam showed the outcomes were maintained. SHM is rare and debilitating, is part of the global burden of disease, and is a major cause of disability in the world. Reports of successful conservative and non-conservative long-term treatments for SHM are rare, and there are no clinical trials showing successful treatments for SHM. This successful case demonstrates preliminary evidence that CBP spinal structural rehabilitation may serve as a treatment option for SHM. Future studies are needed to replicate the findings from this case.
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Affiliation(s)
| | - Jason W Haas
- Research, Chiropractic BioPhysics (CBP) NonProfit, Windsor, USA
| | | | | | - Deed E Harrison
- Physical Medicine and Rehabilitation, Chiropractic BioPhysics (CBP) NonProfit, Eagle, USA
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Saini L, Gunasekaran PK, Tiwari S, Choudhary B, Manjunathan S, Kumar A. Familial hemiplegic migraine in Indian children-a tertiary center experience. J Trop Pediatr 2024; 70:fmae008. [PMID: 38580379 DOI: 10.1093/tropej/fmae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.
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Affiliation(s)
- Lokesh Saini
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India
| | | | - Sarbesh Tiwari
- Department of Diagnostic and Interventional Radiology, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India
| | - Bharat Choudhary
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India
| | - Sujatha Manjunathan
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India
| | - Ashna Kumar
- Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India
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Alfayyadh MM, Maksemous N, Sutherland HG, Lea RA, Griffiths LR. Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and Emerging Approaches. Genes (Basel) 2024; 15:443. [PMID: 38674378 PMCID: PMC11049430 DOI: 10.3390/genes15040443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Migraine is a severe, debilitating neurovascular disorder. Hemiplegic migraine (HM) is a rare and debilitating neurological condition with a strong genetic basis. Sequencing technologies have improved the diagnosis and our understanding of the molecular pathophysiology of HM. Linkage analysis and sequencing studies in HM families have identified pathogenic variants in ion channels and related genes, including CACNA1A, ATP1A2, and SCN1A, that cause HM. However, approximately 75% of HM patients are negative for these mutations, indicating there are other genes involved in disease causation. In this review, we explored our current understanding of the genetics of HM. The evidence presented herein summarises the current knowledge of the genetics of HM, which can be expanded further to explain the remaining heritability of this debilitating condition. Innovative bioinformatics and computational strategies to cover the entire genetic spectrum of HM are also discussed in this review.
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Affiliation(s)
| | | | | | | | - Lyn R. Griffiths
- Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia; (M.M.A.); (N.M.); (H.G.S.); (R.A.L.)
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Wicker C, Roux CJ, Goujon L, de Feraudy Y, Hully M, Brassier A, Bérat CM, Chemaly N, Wiedemann A, Damaj L, Abi-Warde MT, Dobbelaere D, Roubertie A, Cano A, Arion A, Kaminska A, Da Costa S, Bruneel A, Vuillaumier-Barrot S, Boddaert N, Pascreau T, Borgel D, Kossorotoff M, Harroche A, de Lonlay P. Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management. Mol Genet Metab 2023; 140:107674. [PMID: 37542768 DOI: 10.1016/j.ymgme.2023.107674] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 07/29/2023] [Indexed: 08/07/2023]
Abstract
OBJECTIVES Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.
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Affiliation(s)
- Camille Wicker
- Centre de Référence des Maladies Héréditaires du Métabolisme, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, G2M, MetabERN, Paris, France; Centre de Compétence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire de Strasbourg, Strasbourg, France
| | - Charles-Joris Roux
- Université Paris Cité, Paris, France; Service de Radiologie Pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, Paris, France
| | - Louise Goujon
- Centre de Référence des Maladies Héréditaires du Métabolisme, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, G2M, MetabERN, Paris, France
| | - Yvan de Feraudy
- Service de Neurologie Pédiatrique, Hôpital Universitaire de Strasbourg, Strasbourg, France
| | - Marie Hully
- Service de Neurologie Pédiatrique, Médecine physique et réadaptation de l'enfant, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, Paris, France
| | - Anais Brassier
- Centre de Référence des Maladies Héréditaires du Métabolisme, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, G2M, MetabERN, Paris, France
| | - Claire-Marine Bérat
- Centre de Référence des Maladies Héréditaires du Métabolisme, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, G2M, MetabERN, Paris, France
| | - Nicole Chemaly
- Service de Neurologie Pédiatrique, Médecine physique et réadaptation de l'enfant, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, Paris, France
| | - Arnaud Wiedemann
- Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire de Nancy, Nancy, France
| | - Lena Damaj
- Centre de Compétence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire de Rennes, Renne, France
| | - Marie-Thérèse Abi-Warde
- Centre de Compétence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire de Strasbourg, Strasbourg, France; Service de Neurologie Pédiatrique, Hôpital Universitaire de Strasbourg, Strasbourg, France
| | - Dries Dobbelaere
- Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire Jeanne de Flandre de Lille, MetabERN, Lille, France
| | - Agathe Roubertie
- Centre de Compétence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire de Montpellier, Montpellier, France
| | - Aline Cano
- Centre de Référence des Maladies Héréditaires du Métabolisme, service de Neurologie pédiatrique, Hôpital Universitaire d'enfants La Timone de Marseille, MetabERN, Marseille, France
| | - Alina Arion
- Centre de Compétence des Maladies Héréditaires du Métabolisme, Hôpital Universitaire de Caen, Caen, France
| | - Anna Kaminska
- Service d'Exploration Fonctionnelle, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, G2M, MetabERN, Paris, France
| | - Sabrina Da Costa
- Centre de Référence d'Endocrinologie des Maladies Rares, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, Paris, France
| | - Arnaud Bruneel
- Département de Biochimie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Bichat, Paris, France
| | - Sandrine Vuillaumier-Barrot
- Département de Biochimie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Bichat, Paris, France
| | - Nathalie Boddaert
- Université Paris Cité, Paris, France; Service de Radiologie Pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, Paris, France
| | - Tiffany Pascreau
- Laboratoire d'Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Paris, France
| | - Delphine Borgel
- Laboratoire d'Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Paris, France
| | - Manoelle Kossorotoff
- Centre national de référence de l'AVC de l'enfant, Service de Neurologie Pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Inserm U1266, Paris, France
| | - Annie Harroche
- Centre de Référence Maladies Hémorragiques constitutionnelles, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, Paris, France
| | - P de Lonlay
- Centre de Référence des Maladies Héréditaires du Métabolisme, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker-Enfants-Malades, Institut Imagine, G2M, MetabERN, Paris, France; Université Paris Cité, Paris, France; INSERM, Institut Necker-Enfants Malades, France.
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Hanna D, Holland J, Lichtblau N, Maduakor C, Khan F, Kerr T. Know your stroke mimics. Arch Dis Child Educ Pract Ed 2023; 108:152-153. [PMID: 35115313 DOI: 10.1136/archdischild-2021-323223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/11/2021] [Indexed: 11/03/2022]
Affiliation(s)
- Dina Hanna
- Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Jonathon Holland
- Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Nicole Lichtblau
- Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Chinedu Maduakor
- Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Faraan Khan
- Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
- Department of Neuroradiology, Atkinson Morley Regional Neuroscience Centre, St George's University Hospitals NHS foundaton Trust, London, UK
| | - Tim Kerr
- Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
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Alebaji MB, Ani MA, Rozieh SA, Al Shibli AI. Unusual Presentation of a Hemiplegic Migraine in a Seven-Year-Old Child: A Case Report. Cureus 2023; 15:e36726. [PMID: 37123759 PMCID: PMC10131133 DOI: 10.7759/cureus.36726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2023] [Indexed: 03/29/2023] Open
Abstract
In the pediatric population, headache is a common presenting symptom, and migraine is often the diagnosis. A hemiplegic migraine is characterized by an aura and sudden-onset weakness on one side of the body that usually resolves without causing any permanent neurological damage. In this case, we present a seven-year-old male child with a known case of proximal tubular dysfunction (homozygous mutation in the SLC4A4 gene) who presented to the emergency department with a one-day history of weakness on the right side of his body. A few hours after being discharged from the hospital, he began complaining of a severe headache on the left side, accompanied by photophobia, phonophobia, and high fever. Radiology scans and laboratory workup were unremarkable, and encephalitis was ruled out. He was later diagnosed with hemiplegic migraine based on his history and clinical presentation.
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Sanchez Del Rio M, Cutrer FM. Pathophysiology of migraine aura. HANDBOOK OF CLINICAL NEUROLOGY 2023; 198:71-83. [PMID: 38043972 DOI: 10.1016/b978-0-12-823356-6.00016-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Migraine aura occurs in about a third of patients with migraine and consists of a group of transient focal neurological symptoms that appear from 5 to 60min and then resolve prior to or in the early phase of a migraine headache attack. Migraine auras may consist of visual, language, unilateral sensory, or motor symptoms. There has been considerable debate as to the origins of the migrainous aura. Investigations during physiologically induced visual auras suggest that the phenomenon of cortical spreading depression or its human equivalent underpins the migraine aura. Single gene defects have been linked to relatively rare forms of the motor subtypes of aura known as familial hemiplegic migraine (FHM). These include CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3). In the familial hemiplegic forms of migraine, the more typical forms of aura are almost always also present. Despite ample epidemiological evidence of increased heritability of migraine with aura compared to migraine without aura, identification of the specific variants driving susceptibility to the more common forms of aura has been problematic thus far. In the first genome-wide association study (GWAS) that focused migraine with aura, a single SNP rs835740 reached genome-wide significance. Unfortunately, the SNP did show statistical significance in a later meta-analysis which included GWAS data from subsequent studies. Here, we review the clinical features, pathophysiological theories, and currently available potential evidence for the genetic basis of migraine aura.
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11
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Indelicato E, Boesch S. CACNA1A-Related Channelopathies: Clinical Manifestations and Treatment Options. Handb Exp Pharmacol 2023; 279:227-248. [PMID: 36592223 DOI: 10.1007/164_2022_625] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
In the last decade, variants in the Ca2+ channel gene CACNA1A emerged as a frequent aetiology of rare neurological phenotypes sharing a common denominator of variable paroxysmal manifestations and chronic cerebellar dysfunction. The spectrum of paroxysmal manifestations encompasses migraine with hemiplegic aura, episodic ataxia, epilepsy and paroxysmal non-epileptic movement disorders. Additional chronic neurological symptoms range from severe developmental phenotypes in early-onset cases to neurobehavioural disorders and chronic cerebellar ataxia in older children and adults.In the present review we systematically approach the clinical manifestations of CACNA1A variants, delineate genotype-phenotype correlations and elaborate on the emerging concept of an age-dependent phenotypic spectrum in CACNA1A disease. We furthermore reflect on different therapy options available for paroxysmal symptoms in CACNA1A and address open issues to prioritize in the future clinical research.
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Affiliation(s)
- Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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12
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Evers S, Tassorelli C. Migraine with aura. HANDBOOK OF CLINICAL NEUROLOGY 2023; 198:169-186. [PMID: 38043960 DOI: 10.1016/b978-0-12-823356-6.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
This chapter describes the different types of aura including rare aura subtypes such as retinal aura. In addition, aura manifestations not classified in the International Classification of Headache Disorders and auras in headache disorders others than migraine are also described. The differential diagnosis of migraine aura comprises several neurological disorders which should be known to specialists. Migraine aura also has impact on the choice of migraine treatment; recommendations for the treatment of the migraine aura itself are also presented in this chapter.
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Affiliation(s)
- Stefan Evers
- Faculty of Medicine, University of Münster, Münster, Germany; Department of Neurology, Lindenbrunn Hospital, Coppenbrügge, Germany.
| | - Cristina Tassorelli
- Headache Science and Neurorehabilitation Center, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
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Reducing the Burden of Migraine: Safety and Efficacy of CGRP Pathway-Targeted Preventive Treatments. J Clin Med 2022; 11:jcm11154359. [PMID: 35955976 PMCID: PMC9369309 DOI: 10.3390/jcm11154359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/24/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022] Open
Abstract
Migraine is a highly disabling and often chronic neurological disease that affects more than one billion people globally. Preventive migraine treatment is recommended for individuals who have frequent and/or disabling attacks; however, many of the medications used for migraine prevention (e.g., antiepileptics, antidepressants, antihypertensives) were not specifically developed for migraine, and often have limited efficacy or poor tolerability. Four monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, which is believed to play a crucial role in the pathophysiology of migraine, have been approved by the US Food and Drug Administration for the preventive treatment of migraine in adults. All four migraine-specific treatments have demonstrated efficacy based on reductions in monthly days with migraine for patients with both episodic and chronic migraine, including those with comorbidities. They have also demonstrated favorable safety and tolerability profiles. Based on these accounts, CGRP pathway-targeted monoclonal antibodies have the potential to revolutionize preventive treatment for patients with migraine.
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Yuan X, Zheng Y, Gao F, Sun W, Wang Z, Zhao G. Case Report: A Novel CACNA1A Mutation Caused Flunarizine-Responsive Type 2 Episodic Ataxia and Hemiplegic Migraine With Abnormal MRI of Cerebral White Matter. Front Neurol 2022; 13:899813. [PMID: 35677330 PMCID: PMC9168224 DOI: 10.3389/fneur.2022.899813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 04/21/2022] [Indexed: 11/23/2022] Open
Abstract
Episodic ataxia type 2 (EA2) is one autosomal-dominant neurological disorder characterized by debilitating attacks of ataxia. It is mainly caused by loss-of-function mutations of the CACNA1A gene, which encodes the pore-forming α1A subunit of Cav2.1 (P/Q type voltage-gated calcium channel). Sporadic hemiplegic migraine (SHM) is another rare disease involving CACNA1A variants, which seldom coexists with EA2. Here we report a novel pathogenic mutation in CACNA1A (c.3836dupA, exon 23, p.Y1279X) of a 16-year-old female, who complained about paroxysmal dizziness, headache, and unsteady gait. Her brain MRI revealed a slightly atrophic cerebellum and numerous asymptomatic hyperintense lesions of the cerebral white matter. The diagnosis of EA2 combined with SHM was made. Administration of 5-mg flunarizine once daily at night effectively reduced the attacks and attenuated her symptoms for a month.
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Affiliation(s)
| | | | | | | | | | - Guiping Zhao
- Department of Neurology, Peking University First Hospital, Beijing, China
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15
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Chua AL, Mehla S, Orlova YY. Drug Safety in Episodic Migraine Management in Adults. Part 2: Preventive Treatments. Curr Pain Headache Rep 2022; 26:493-504. [PMID: 35587859 DOI: 10.1007/s11916-022-01051-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE OF REVIEW The aim of this review is to aid in decision-making when choosing safe and effective options for preventive migraine medications. RECENT FINDINGS In Part 2, we have compiled clinically relevant safety considerations for commonly used migraine prophylactic treatments. Preventive treatment of episodic migraine includes nonspecific and migraine-specific drugs. While medications from several pharmacological classes-such as anticonvulsants, beta-blockers, and antidepressants-have an established efficacy in migraine prevention, they are associated with a number of side effects. The safety of migraine-specific treatments such as anti-CGRP monoclonal antibodies and gepants are also discussed. This review highlights safety concerns of commonly used migraine prophylactic agents and offers suggestions on how to mitigate those risks.
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Affiliation(s)
- Abigail L Chua
- Geisinger Health Systems, Neurology, 1000 E. Mountain Boulevard, Wilkes-Barre, PA, 18711, USA.
| | - Sandhya Mehla
- Ayer Neurosciences Institute, Hartford HealthCare Medical Group, University of Connecticut School of Medicine, Norwich, CT, USA
| | - Yulia Y Orlova
- Neurology Department, University of Florida, Gainesville, USA
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16
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Abstract
Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT1B/1D receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1F receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management.
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17
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Hasırcı Bayır BR, Tutkavul K, Eser M, Baykan B. Epilepsy in patients with familial hemiplegic migraine. Seizure 2021; 88:87-94. [PMID: 33839563 DOI: 10.1016/j.seizure.2021.03.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/26/2021] [Accepted: 03/28/2021] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVE The coexistence of epilepsy in familial hemiplegic migraine (FHM) has not been reviewed systematically. We investigated the associations of epilepsy in patients with FHM with CACNA1A, ATP1A2, SCN1A or PRRT2 mutations along with clinical and genetic data. MATERIALS AND METHODS We performed a search in the PubMed bibliographic database and the Cochrane Library was screened for eligible studies, from April 1997 to December 2020. Additionally, Online Mendelian Inheritance in Man (OMIM) was searched for mutations in the CACNA1A, ATP1A2, SCN1A and PRRT2 genes. Brief reports, letters, and original articles about FHM and epilepsy were included in the review if their mutations and clinical course of diseases were identified. RESULTS Of the included patients with FHM whose information could be accessed, there were 28 families and 195 individuals, 78 of whom had epilepsy; 30 patients had focal epilepsy and 30 patients had generalized epilepsy. All mutations except ATP1A2, which could not be evaluated due to insufficient data, revealed first epilepsy then HM. In 60 patients for whom the epilepsy prognosis was evaluated, only 3.5% of patients were drug-resistant, and the remainder had a self-limited course or responded to anti-epileptic drug treatment. CONCLUSION Mutations in all three and possibly four FHM genes can cause epilepsy. Contrary to our expectations, the well-known epilepsy gene SCN1A mutations are not the leading cause; the highest number of cases associated with epilepsy belongs to the ATP1A2 mutation. Drug-resistant forms of epilepsy are rare in all FHM mutations, and this information is important for counseling patients.
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Affiliation(s)
- Buse Rahime Hasırcı Bayır
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; Department of Neurology, Haydarpaşa Numune Research and Training Hospital, Istanbul, Turkey.
| | - Kemal Tutkavul
- Department of Neurology, Haydarpaşa Numune Research and Training Hospital, Istanbul, Turkey.
| | - Metin Eser
- Department of Medical Genetics, Ümraniye Research and Training Hospital, Istanbul, Turkey.
| | - Betül Baykan
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; Neuroscience Department, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
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18
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Shapiro HF, Lebel A. Pediatric Episodic Migraine with Aura: A Unique Entity? CHILDREN-BASEL 2021; 8:children8030228. [PMID: 33802676 PMCID: PMC8002456 DOI: 10.3390/children8030228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/13/2021] [Accepted: 03/15/2021] [Indexed: 11/16/2022]
Abstract
Migraine headache is a common cause of pain and disability in children and adolescents and is a major contributor to frequently missed school days and limitations in activities. Of children and adolescents with migraine headache, approximately one-third have migraine with aura (MA). MA is often considered to be similar to migraine without aura (MO), and thus, many studies do not stratify patients based on the presence of aura. Because of this, treatment recommendations are often analogous between MA and MO, with a few notable exceptions. The purpose of this review is to highlight the current evidence demonstrating the unique pathophysiology, clinical characteristics, differential diagnosis, co-morbidities, and treatment recommendations and responses for pediatric MA.
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Affiliation(s)
- Hannah F.J. Shapiro
- Department of Child Neurology, Boston Children’s Hospital, Boston, MA 02115, USA;
| | - Alyssa Lebel
- Division of Pain Medicine, Department of Anesthesiology, Boston Children’s Hospital, Boston, MA 02115, USA
- Correspondence:
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Indelicato E, Boesch S. From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing. Front Neurol 2021; 12:639994. [PMID: 33737904 PMCID: PMC7960780 DOI: 10.3389/fneur.2021.639994] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/08/2021] [Indexed: 12/15/2022] Open
Abstract
Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.
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Affiliation(s)
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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20
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Serrano M. Stroke-Like Episodes in PMM2-CDG: When the Lack of Other Evidence Is the Only Evidence. Front Pediatr 2021; 9:717864. [PMID: 34708008 PMCID: PMC8542667 DOI: 10.3389/fped.2021.717864] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/17/2021] [Indexed: 12/20/2022] Open
Abstract
Phosphomannomutase 2 deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. PMM2-CDG patients develop chronic cerebellar atrophy as a neurological hallmark. However, other acute neurological phenomena such as stroke-like episodes (SLE), epilepsy, migraine, and cerebrovascular events, may also occur, and they are frequently the cause of disability and impaired quality of life. Among these, SLE are among the most stressful situations for families and doctors, as their risk factors are not known, their underlying pathomechanisms remain undiscovered, and clinical guidelines for diagnosis, prevention, and treatment are lacking. In this paper, the recent SLE experiences of two PMM2-CDG patients are examined to provide clinical clues to help improve diagnosis through a clinical constellation of symptoms and a clinical definition, but also to support a neuroelectrical hypothesis as an underlying mechanism. An up-to-date literature review will help to identify evidence-based and non-evidence-based management recommendations. Presently neuropediatricians and neurologists are not capable of diagnosing stroke-like episodes in an unequivocal way, so there is still a need to perform invasive studies (to rule out other acute diseases) that may, in the end, prove unnecessary or even harmful. However, reaching a correct and early diagnosis would lead not only to avoidance of invasive tests but also to better recognition, management, and understanding of the disease itself. There is a great need for understanding of SLE that may ultimately be very informative for the detection of patients at risk, and the future development of preventive and management measures.
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Affiliation(s)
- Mercedes Serrano
- Department of Neuropediatric, Institut de Recerca Hospital Sant Joan de Déu, Barcelona, Spain.,U-703 Center for Biomedical Research on Rare Diseases (CIBER-ER), Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain
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21
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Lo Y, Wee S, Zhao Y, Narasimhalu K. Interictal hemodynamic abnormality during motor activation in sporadic hemiplegic migraine: An explorative study. J Neurol Sci 2020; 418:117148. [DOI: 10.1016/j.jns.2020.117148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 10/23/2022]
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22
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Pediatric Migraine Phenomena and Variants: Don't Let Them Go Over Your Head. Curr Pain Headache Rep 2020; 24:47. [PMID: 32671489 DOI: 10.1007/s11916-020-00879-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE OF REVIEW Primary care providers, general pediatric neurologists, and other related subspecialty providers require a clear understanding of pediatric migraine with typical aura and its variants. RECENT FINDINGS We highlight some of the genetic mutations known to contribute to specific types of migraine with aura, discuss the ophthalmologic phenomena of migraine and call attention to some of the earliest manifestations of migraine in children, many of which have correlates in adulthood. While the majority of headaches in children are migraine with or without aura or tension type, many migraine and aura variants exist. Early and accurate diagnosis of episodic syndromes associated with migraine, as defined by the 2018 ICHD-3 criteria, can help to reduce unnecessary imaging, referrals, cost and anxiety, thereby benefiting patients and their families.
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23
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Di Stefano V, Rispoli MG, Pellegrino N, Graziosi A, Rotondo E, Napoli C, Pietrobon D, Brighina F, Parisi P. Diagnostic and therapeutic aspects of hemiplegic migraine. J Neurol Neurosurg Psychiatry 2020; 91:764-771. [PMID: 32430436 PMCID: PMC7361005 DOI: 10.1136/jnnp-2020-322850] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/22/2020] [Accepted: 04/24/2020] [Indexed: 01/25/2023]
Abstract
Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability. Motor symptoms usually last <72 hours and are associated with visual or sensory manifestations, speech impairment or brainstem aura. HM can occur as a sporadic HM or familiar HM with an autosomal dominant mode of inheritance. Mutations in CACNA1A, ATP1A2 and SCN1A encoding proteins involved in ion transport are implicated. The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity. We reviewed epidemiology, clinical presentation, diagnostic assessment, differential diagnosis and treatment of HM to offer the best evidence of this rare condition. The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation. The management relies on the control of triggering factors and even hospitalisation in case of long-lasting auras. As HM is a rare condition, there are no randomised controlled trials, but the evidence for the treatment comes from small studies.
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Affiliation(s)
- Vincenzo Di Stefano
- Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Sicilia, Italy
| | - Marianna Gabriella Rispoli
- Department of Neuroscience Imaging and Clinical Sciences, 'G. d'Annunzio' University, Universita degli Studi Gabriele d'Annunzio Chieti e Pescara, Chieti Scalo, Chieti, Italy
| | - Noemi Pellegrino
- Pediatrics, University Gabriele d'Annunzio of Chieti Pescara Department of Medicine and Aging Science, Chieti, Abruzzo, Italy
| | - Alessandro Graziosi
- Pediatrics, University Gabriele d'Annunzio of Chieti Pescara Department of Medicine and Aging Science, Chieti, Abruzzo, Italy
| | - Eleonora Rotondo
- Pediatrics, University Gabriele d'Annunzio of Chieti Pescara Department of Medicine and Aging Science, Chieti, Abruzzo, Italy
| | - Christian Napoli
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza University of Rome, Roma, Lazio, Italy
| | - Daniela Pietrobon
- Department of Biomedical Sciences & Padova Neuroscience Center, University of Padova, Padova, Italy.,CNR Neuroscience Institute, Padova, Italy
| | - Filippo Brighina
- Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Palermo, Sicilia, Italy
| | - Pasquale Parisi
- Dipartimento di Neuroscienze Salute Mentale e Organi di Senso (NESMOS), University of Rome La Sapienza Faculty of Medicine and Psychology, Roma, Lazio, Italy
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24
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de Boer I, Terwindt GM, van den Maagdenberg AMJM. Genetics of migraine aura: an update. J Headache Pain 2020; 21:64. [PMID: 32503413 PMCID: PMC7275514 DOI: 10.1186/s10194-020-01125-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/19/2020] [Indexed: 12/20/2022] Open
Abstract
Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura.
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Affiliation(s)
- Irene de Boer
- Department of Neurology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Gisela M Terwindt
- Department of Neurology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Arn M J M van den Maagdenberg
- Department of Neurology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands. .,Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.
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25
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Tietjen GE, Maly EF. Migraine and Ischemic Stroke in Women. A Narrative Review. Headache 2020; 60:843-863. [DOI: 10.1111/head.13796] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 03/07/2020] [Accepted: 03/08/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Gretchen E. Tietjen
- Department of Neurology University of Toledo College of Medicine and Life Sciences Toledo OH USA
| | - Emily F. Maly
- Department of Neurology University of Toledo College of Medicine and Life Sciences Toledo OH USA
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26
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Gauquelin L, Hawkins C, Tam EWY, Miller SP, Yoon G. Pearls & Oy-sters: Fatal brain edema is a rare complication of severe CACNA1A-related disorder. Neurology 2020; 94:631-634. [PMID: 32170034 DOI: 10.1212/wnl.0000000000009223] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Laurence Gauquelin
- From the Division of Clinical and Metabolic Genetics (L.G., G.Y.) and Division of Neurology (L.G., E.W.Y.T., S.P.M., G.Y.), Department of Paediatrics, and Division of Pathology, Department of Paediatric Laboratory Medicine (C.H.), The Hospital for Sick Children, University of Toronto, Canada
| | - Cynthia Hawkins
- From the Division of Clinical and Metabolic Genetics (L.G., G.Y.) and Division of Neurology (L.G., E.W.Y.T., S.P.M., G.Y.), Department of Paediatrics, and Division of Pathology, Department of Paediatric Laboratory Medicine (C.H.), The Hospital for Sick Children, University of Toronto, Canada
| | - Emily W Y Tam
- From the Division of Clinical and Metabolic Genetics (L.G., G.Y.) and Division of Neurology (L.G., E.W.Y.T., S.P.M., G.Y.), Department of Paediatrics, and Division of Pathology, Department of Paediatric Laboratory Medicine (C.H.), The Hospital for Sick Children, University of Toronto, Canada
| | - Steven P Miller
- From the Division of Clinical and Metabolic Genetics (L.G., G.Y.) and Division of Neurology (L.G., E.W.Y.T., S.P.M., G.Y.), Department of Paediatrics, and Division of Pathology, Department of Paediatric Laboratory Medicine (C.H.), The Hospital for Sick Children, University of Toronto, Canada
| | - Grace Yoon
- From the Division of Clinical and Metabolic Genetics (L.G., G.Y.) and Division of Neurology (L.G., E.W.Y.T., S.P.M., G.Y.), Department of Paediatrics, and Division of Pathology, Department of Paediatric Laboratory Medicine (C.H.), The Hospital for Sick Children, University of Toronto, Canada.
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Abstract
Purpose of review Migraine is a primary headache disorder and one of the most common and disabling neurological diseases worldwide. Genome-wide association studies have identified ≈40 genetic loci associated with migraine. How these and other genetic findings are used to expand our knowledge on the pathophysiological mechanism of common migraine and rare migraine variants will be discussed. Recent findings The genetic load, based on common polygenic variation, is higher in familial migraine cases than in nonfamilial cases, and higher for migraine with aura and hemiplegic migraine. Migraine shares common genetic variant risks with depression. Specific clinical features of common migraine seem to be determined by genetic factors. A stronger family history of migraine is associated with lower age-at-onset, higher frequency and number of medication days and the migraine with aura subtype. Mild hemiplegic migraine is likely caused by complex polygenic interaction of multiple gene variants and environmental factors, like in common migraine subtypes. Phenotypical features in hemiplegic migraine patients may guide physicians in providing adequate genetic counseling. Summary Integration of genetic, phenotypic and epigenetic data will help to identify the biological mechanisms by which genetic factors contribute to migraine pathogenesis. Recent studies show the impact of genetics on clinical features and comorbidities in migraine and may guide clinicians to an adequate genetic advice for patients.
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Carnovale C, Dassano A, Mosini G, Mazhar F, D'Addio F, Pozzi M, Radice S, Fiorina P, Clementi E. The β-cell effect of verapamil-based treatment in patients with type 2 diabetes: a systematic review. Acta Diabetol 2020; 57:117-131. [PMID: 31172294 DOI: 10.1007/s00592-019-01370-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/17/2019] [Indexed: 12/22/2022]
Abstract
AIMS The possibility that verapamil has new beneficial effects in diabetic patients in terms of an improvement in glycometabolic control has been put forward recently in several studies. However, to date the issue is still under debate. We conducted the first systematic review examining the impact of verapamil-based treatment on glycometabolic outcomes, in type 2 diabetes (T2D) patients. METHODS We searched the PubMed, MEDLINE, Embase, Cochrane and ClinicalTrials.gov up to 9 October 2018, for all studies evaluating whether verapamil-based treatment is associated with changes in glycated haemoglobin (HbA1c), fasting plasma glucose levels, glucose and C-peptide areas from baseline in humans, without restrictions for study type. RESULTS Plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (mean change - 13 ± 5.29; P = 0.049); HbA1c values were instead not affected by the drug (mean change - 0.10 ± 0.12; P = 0.453). In five studies, groups exposed to verapamil achieved lower value of glycometabolic outcomes: comparison with values recorded in control groups showed a significant difference, in terms of both HbA1c and plasma glucose levels. CONCLUSIONS Despite the fact that plasma glucose levels were lowered significantly by verapamil-based treatment in patients with T2D (the HbA1c values were not affected by the drug), the clinical significance of the glycometabolic response induced by verapamil-based treatment remains unclear due to the high variety of sample size and type of studies presently available. Further experimental and clinical trials are needed to clarify unambiguously the role of verapamil in metabolic control.
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Affiliation(s)
- Carla Carnovale
- Unit Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Via GB Grassi 74, 20157, Milan, Italy.
| | - Alice Dassano
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, Università di Milano, 20157, Milan, Italy
| | - Giulia Mosini
- Unit Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Via GB Grassi 74, 20157, Milan, Italy
| | - Faizan Mazhar
- Unit Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Via GB Grassi 74, 20157, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, Università di Milano, 20157, Milan, Italy
| | - Marco Pozzi
- Scientific Institute IRCCS Eugenio Medea, 23842, Bosisio Parini, Lecco, Italy
| | - Sonia Radice
- Unit Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Via GB Grassi 74, 20157, Milan, Italy
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, Università di Milano, 20157, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, 20157, Milan, Italy
| | - Emilio Clementi
- Unit Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Via GB Grassi 74, 20157, Milan, Italy
- Scientific Institute IRCCS Eugenio Medea, 23842, Bosisio Parini, Lecco, Italy
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Monseur BC, Anastasio HB, Haddad A, Al‐Kouatly HB. Review of familial hemiplegic migraine, successful outcome in a pregnant patient. Clin Case Rep 2019; 7:2495-2499. [PMID: 31893087 PMCID: PMC6935667 DOI: 10.1002/ccr3.2513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/23/2019] [Accepted: 10/11/2019] [Indexed: 12/30/2022] Open
Abstract
As the field of neurogenetics is expanding rapidly and variant classification criteria evolve, genetic variants in databases are re-evaluated overtime allowing updated classifications of pathogenicity predication. When caring for patients with genetic disorders, it is important to obtain the original genetic report and also consider an updated reanalysis.
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Affiliation(s)
- Brent C. Monseur
- Department of Obstetrics and GynecologySidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPennsylvania
| | - Hannah B. Anastasio
- Division of Maternal Fetal MedicineDepartment of Obstetrics and GynecologySidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPennsylvania
| | - Andrew Haddad
- Division of Maternal Fetal MedicineDepartment of Obstetrics and GynecologyMedStar Washington Hospital CenterWashingtonDistrict of Columbia
| | - Huda B. Al‐Kouatly
- Division of Maternal Fetal MedicineDepartment of Obstetrics and GynecologySidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphiaPennsylvania
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30
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Rispoli MG, Di Stefano V, Mantuano E, De Angelis MV. Novel missense mutation in the ATP1A2 gene associated with atypical sporapedic hemiplegic migraine. BMJ Case Rep 2019; 12:12/10/e231129. [PMID: 31586957 DOI: 10.1136/bcr-2019-231129] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Hemiplegic migraine (HM) is a rare subtype of migraine with aura in which attacks include transient motor weakness or hemiparesis that can last several days. HM is linked to mutations in three different genes, CACNA1A, ATP1A2 and SCN1A, which encode for ion transporters. The clinical spectrum includes atypical symptoms such as impaired consciousness, epileptic seizures, permanent cerebellar ataxia or mental retardation. We describe a novel mutation found in the ATP1A2 gene in a patient with late-onset HM. His attacks were characterised by motor weakness associated with altered mental status, diplopia and ataxia. He also showed up MRI abnormalities and incomplete response to prophylactic therapy with verapamil. Late-onset HM should be considered among the possible causes of focal neurological deficits even in older patients with cerebrovascular risk factors when a stroke appears to be more likely.
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Affiliation(s)
| | - Vincenzo Di Stefano
- Department of Neuroscience, Imaging and Clinical Sciences, "G. d' annunzio" University, Chieti, Italy
| | - Elide Mantuano
- Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy
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31
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Yang XY, Du HP, Xu Y. A case of late-onset sporadic hemiplegic migraine. J Int Med Res 2019; 47:5278-5280. [PMID: 31510845 PMCID: PMC6833420 DOI: 10.1177/0300060519873468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Sporadic hemiplegic migraine is a rare form of migraine headache with aura. We herein report a case of visual impairment, dizziness, and motor weakness in a patient who had experienced recurrent headache attacks with aura including flickering spots and blurred vision for 20 years, Electroencephalography, cerebrospinal fluid analysis, and brain imaging findings were normal. The patient gradually recovered after treatment with nonsteroidal anti-inflammatory drugs and flunarizine.
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Affiliation(s)
- Xiu-Yan Yang
- Department of Neurology, Suzhou Ninth People's Hospital, Suzhou, Jiangsu, China
| | - Hua-Ping Du
- Department of Neurology, Suzhou Ninth People's Hospital, Suzhou, Jiangsu, China
| | - Yuan Xu
- Department of Neurology, Suzhou Ninth People's Hospital, Suzhou, Jiangsu, China
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32
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Nagarajan E, Bollu PC, Manjamalai S, Yelam A, Qureshi AI. White Matter Hyperintensities in Patients with Sporadic Hemiplegic Migraine. J Neuroimaging 2019; 29:730-736. [PMID: 31304994 DOI: 10.1111/jon.12656] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 06/26/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND AND PURPOSE To identify the differences in overall occurrence, location, and disease burden of white matter hyperintensities (WMH) in patients with sporadic hemiplegic migraine (SHM) and patients with migraine headaches. METHODS We included patients who met diagnostic criteria proposed by the third International Classification of Headache Disorders (ICHD-3) for SHM and migraine headache. WMHs were identified using T2 fluid-attenuated inversion recovery axial sequence and classified based upon the location. The disease burden was assessed using Scheltens visual rating scale. RESULTS Fifty patients met the diagnostic criteria for SHM and 100 patients for migraine headache. Patients in the study group were similar to the control group in terms of age (47.7 ± 12.2 years vs. 48.17 ± 9.7 years; P = .814) and gender (M: F; 14:36 vs. M: F 25:75; P = .693). WMH were found in 28 (56%) patients with SHM and 44 (44%) in patients with migraine headache. The proportion of patients with WMH was not different between the two groups (P = .166). On univariate analysis, the proportion of patients with WMH in parietal, occipital, and infratentorial regions was higher in patients with SHM. White matter burden determined by visual rating scale and proportion of patients with lesions ≥5 mm in diameter was also significantly higher in patients with SHM. On multivariate analysis, the WMH occurrence in the parietal lobe (P = .043) was found to be significantly higher in SHM. CONCLUSIONS The WMH occurrence in patients with SHM is significantly more in the parietal lobe when compared to those with migraine headaches. WMH burden was also higher in patients with SHM, and larger white matter lesions occurred more frequently in these patients with SHM (compared to ordinary migraineurs).
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Affiliation(s)
| | - Pradeep C Bollu
- Department of Neurology, University of Missouri, Columbia, Missouri
| | | | - Anudeep Yelam
- Department of Neurology, University of Missouri, Columbia, Missouri
| | - Adnan I Qureshi
- Department of Neurology, University of Missouri, Columbia, Missouri.,Zeenat Qureshi Stroke Institute, St. Cloud, Minnesota
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33
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Sutherland HG, Albury CL, Griffiths LR. Advances in genetics of migraine. J Headache Pain 2019; 20:72. [PMID: 31226929 PMCID: PMC6734342 DOI: 10.1186/s10194-019-1017-9] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 05/24/2019] [Indexed: 02/06/2023] Open
Abstract
Background Migraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology. Findings Migraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants. With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology. Conclusions The complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.
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Affiliation(s)
- Heidi G Sutherland
- Genomics Research Centre, Institute of Health and Biomedical Innovation. School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia
| | - Cassie L Albury
- Genomics Research Centre, Institute of Health and Biomedical Innovation. School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia
| | - Lyn R Griffiths
- Genomics Research Centre, Institute of Health and Biomedical Innovation. School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD, Australia.
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34
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Balakrishnan P, Katakam PK, Hegde AP. Familial hemiplegic migraine in a child with seizure disorder: clinical history is the key to diagnosis. BMJ Case Rep 2019; 12:12/3/e228687. [PMID: 30914414 DOI: 10.1136/bcr-2018-228687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Headache is a common presenting complaint in the paediatric population, with often migraine being a clinical diagnosis. Hemiplegic migraine is characterised by aura, sudden onset weakness of one side of the body which usually recovers without any residual neurological deficit. We report a child with a history of seizure disorder, well controlled and off medication for 3 years, who presented with a headache, aura and transient hemiplegia. Similar history in the patient's mother suggests the diagnosis of familial hemiplegic migraine. We would like to emphasise the importance of detailed history as an important aid in the diagnosis of neurological disorders in children.
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Affiliation(s)
- Pranav Balakrishnan
- Department of Paediatrics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Phalguna Kousika Katakam
- Department of Paediatrics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Asha P Hegde
- Department of Paediatrics, Manipal Melaka Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
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35
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Rau JC, Dodick DW. Other Preventive Anti-Migraine Treatments: ACE Inhibitors, ARBs, Calcium Channel Blockers, Serotonin Antagonists, and NMDA Receptor Antagonists. Curr Treat Options Neurol 2019; 21:17. [PMID: 30880363 DOI: 10.1007/s11940-019-0559-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE OF REVIEW Migraine causes more years of life lived with disability than almost any other condition in the world and can significantly impact the lives of individuals with migraine, their families, and society. The use of medication for the prevention of migraine is an integral component to reducing disability caused by migraine. There are many different drug classes that have been investigated and shown efficacy in migraine prophylaxis. This article examines several of the classes of medications that are used for migraine preventive treatment, specifically, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, serotonin antagonists, alpha-adrenergic agonists, and N-methyl-D-aspartic acid receptor antagonists. RECENT FINDINGS There have been randomized control trials investigating medications in these drug classes since the most recent guidelines for migraine prevention in adults were published by the American Academy of Neurology, American Headache Society, and the Canadian Headache Society. In these investigations, enalapril, candesartan, and memantine all demonstrated efficacy for migraine prevention. The evidence for these and the aforementioned drug classes are reviewed. When oral medications are being selected for migraine prevention, comorbid and coexistent medical conditions, concomitant medications, patient preference, and pregnancy and breast-feeding plans should be considered. Within the drug classes discussed, memantine and candesartan have a moderate level of evidence for efficacy.
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Affiliation(s)
- Jill C Rau
- Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ, 85259, USA
| | - David W Dodick
- Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ, 85259, USA.
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36
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Trahan EM, Mercado JM. Familial Hemiplegic Migraines and Baseline Neuropsychological Testing: A Case Report. Headache 2019; 59:917-923. [PMID: 30869161 DOI: 10.1111/head.13505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2019] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To explore the neuropsychological correlates and implications of familial hemiplegic migraines (FHMs). BACKGROUND FMH is a rare, autosomal dominant subtype of migraine that only occurs in 0.01% of the population. Little is known about the neuropsychological impact of FHMs; however, cognitive impairment associated with cerebellar syndrome has been identified in some cases. METHOD A single case study involving a 24-year-old male who recently endured an atypical, prolonged FHM episode. RESULTS The patient's overall neuropsychological functioning was intact with low average semantic fluency and processing speed, and mild indications of executive dysfunction. CONCLUSION Baseline and serial neuropsychological testing in individuals with FHM may help identify the potential progression and course of cognitive impairment associated with this condition.
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37
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Shao N, Zhang H, Wang X, Zhang W, Yu M, Meng H. Familial Hemiplegic Migraine Type 3 (FHM3) With an SCN1A Mutation in a Chinese Family: A Case Report. Front Neurol 2018; 9:976. [PMID: 30498473 PMCID: PMC6249337 DOI: 10.3389/fneur.2018.00976] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/29/2018] [Indexed: 01/03/2023] Open
Abstract
Familial hemiplegic migraine (FHM) is a rare, monogenic, autosomal dominant subtype of migraine, in which three genes, CACNA1A, ATP1A2, and SCN1A, are currently known to be involved. The familial hemiplegic migraine type 3 (FHM3) is seldom caused by mutations in SCN1A. Here, we report a rare case of an SCN1A mutation leading to FHM3 in a Chinese family. This case report describes a 62-year-old female patient that was admitted to our clinic. She presented with recurrent attacks of hemiplegic migraine. Her symptoms were first suspicious of a transient ischemic attack (TIA), but they were eventually diagnosed as FHM with a c.4495T>C mutation being found in the SCN1A gene. This case highlights that when a patient presents at the clinic with TIA symptoms associated with migraine, the diagnosis of an FHM should be considered and a genetic test is indicated. The identification of SCN1A gene mutations may help us to further understand the FHM pathophysiology.
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Affiliation(s)
- Na Shao
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China
| | - Haining Zhang
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China
| | - Xue Wang
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China
| | - Wuqiong Zhang
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China
| | - Miaomiao Yu
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China
| | - Hongmei Meng
- Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, China
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38
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Vgontzas A, Burch R. Episodic Migraine With and Without Aura: Key Differences and Implications for Pathophysiology, Management, and Assessing Risks. Curr Pain Headache Rep 2018; 22:78. [PMID: 30291554 DOI: 10.1007/s11916-018-0735-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW To review the pathophysiologic, epidemiologic, and clinical evidence for similarities and differences between migraine with and without aura. RECENT FINDINGS The ICHD-3 has recently refined the diagnostic criteria for aura to include positive symptomatology, which better differentiates aura from TIA. Although substantial evidence supports cortical spreading depression as the cause of visual aura, the role (if any) of CSD in headache pain is not well understood. Recent imaging evidence suggests a possible hypothalamic origin for a headache attack, but further research is needed. Migraine with aura is associated with a modest increase in the risk of ischemic stroke. The etiology for this association remains unclear. There is a paucity of evidence regarding treatments specifically aimed at the migraine with aura subtype, or whether migraine with vs without aura responds to treatment differently. Migraine with typical aura is therefore often treated similarly to migraine without aura. Lamotrigine, daily aspirin, and flunarizine have evidence for efficacy in prevention of migraine with aura, and magnesium, ketamine, furosemide, and single-pulse transcranial magnetic stimulation have evidence for use as acute treatments. Although triptans have traditionally been contraindicated in hemiplegic migraine and migraine with brainstem aura, this prohibition is being reconsidered in the face of evidence suggesting that use may be safe. The debate as to whether migraine with and without aura are different entities is ongoing. In an era of sophisticated imaging, genetic advancement, and ongoing clinical trials, efforts to answer this question are likely to yield important and clinically meaningful results.
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Affiliation(s)
- Angeliki Vgontzas
- Graham Headache Center, Brigham and Women's Hospital, Harvard Medical School, 1153 Centre St Suite 4H, Jamaica Plain, Boston, MA, 02130, USA
| | - Rebecca Burch
- Graham Headache Center, Brigham and Women's Hospital, Harvard Medical School, 1153 Centre St Suite 4H, Jamaica Plain, Boston, MA, 02130, USA.
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Indelicato E, Nachbauer W, Karner E, Eigentler A, Wagner M, Unterberger I, Poewe W, Delazer M, Boesch S. The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature. Eur J Neurol 2018; 26:66-e7. [PMID: 30063100 DOI: 10.1111/ene.13765] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/24/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND PURPOSE CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. METHODS Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. RESULTS Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. CONCLUSIONS Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.
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Affiliation(s)
- E Indelicato
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - W Nachbauer
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - E Karner
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - A Eigentler
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - M Wagner
- Department of Neuroradiology, Innsbruck Medical University, Innsbruck, Austria
| | - I Unterberger
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - W Poewe
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - M Delazer
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
| | - S Boesch
- Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
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40
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Brusich DJ, Spring AM, James TD, Yeates CJ, Helms TH, Frank CA. Drosophila CaV2 channels harboring human migraine mutations cause synapse hyperexcitability that can be suppressed by inhibition of a Ca2+ store release pathway. PLoS Genet 2018; 14:e1007577. [PMID: 30080864 PMCID: PMC6095605 DOI: 10.1371/journal.pgen.1007577] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 08/16/2018] [Accepted: 07/20/2018] [Indexed: 11/28/2022] Open
Abstract
Gain-of-function mutations in the human CaV2.1 gene CACNA1A cause familial hemiplegic migraine type 1 (FHM1). To characterize cellular problems potentially triggered by CaV2.1 gains of function, we engineered mutations encoding FHM1 amino-acid substitutions S218L (SL) and R192Q (RQ) into transgenes of Drosophila melanogaster CaV2/cacophony. We expressed the transgenes pan-neuronally. Phenotypes were mild for RQ-expressing animals. By contrast, single mutant SL- and complex allele RQ,SL-expressing animals showed overt phenotypes, including sharply decreased viability. By electrophysiology, SL- and RQ,SL-expressing neuromuscular junctions (NMJs) exhibited enhanced evoked discharges, supernumerary discharges, and an increase in the amplitudes and frequencies of spontaneous events. Some spontaneous events were gigantic (10-40 mV), multi-quantal events. Gigantic spontaneous events were eliminated by application of TTX-or by lowered or chelated Ca2+-suggesting that gigantic events were elicited by spontaneous nerve firing. A follow-up genetic approach revealed that some neuronal hyperexcitability phenotypes were reversed after knockdown or mutation of Drosophila homologs of phospholipase Cβ (PLCβ), IP3 receptor, or ryanodine receptor (RyR)-all factors known to mediate Ca2+ release from intracellular stores. Pharmacological inhibitors of intracellular Ca2+ store release produced similar effects. Interestingly, however, the decreased viability phenotype was not reversed by genetic impairment of intracellular Ca2+ release factors. On a cellular level, our data suggest inhibition of signaling that triggers intracellular Ca2+ release could counteract hyperexcitability induced by gains of CaV2.1 function.
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Affiliation(s)
- Douglas J. Brusich
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
| | - Ashlyn M. Spring
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, United States of America
| | - Thomas D. James
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, United States of America
| | - Catherine J. Yeates
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, United States of America
| | - Timothy H. Helms
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
| | - C. Andrew Frank
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, United States of America
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA, United States of America
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41
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Karsan N, Palethorpe D, Rattanawong W, Marin JC, Bhola R, Goadsby PJ. Flunarizine in migraine-related headache prevention: results from 200 patients treated in the UK. Eur J Neurol 2018. [PMID: 29512871 DOI: 10.1111/ene.13621] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND PURPOSE For over 20 years, as a group we have been using flunarizine in primary headache disorders. Flunarizine is widely used in Europe, but not licensed in the UK. In September 2014, the National Institute for Clinical Excellence published supportive guidelines for flunarizine use in migraine, based on randomized controlled evidence that it is as effective as propranolol and topiramate in adults. METHODS We reviewed a cohort of adult patients (n = 200) treated with flunarizine from our practice. The clinical information of these patients, i.e. diagnosis, dose, efficacy, side effects and duration of treatment, was collected. RESULTS The most common indication for flunarizine use was chronic migraine, followed by migraine with aura, sporadic hemiplegic migraine, familial hemiplegic migraine and new daily persistent headache with migrainous features. Flunarizine was generally effective, with only 24% (n = 47) of patients reporting no clinical effect. The most common dose used was 10 mg per day. Duration of treatment information was available for 39% (n = 78) of patients. Of these patients, 64% (n = 50) continued treatment for more than 1 year. Doses up to 15 mg were generally well tolerated, with only 10.5% (n = 21) of patients stopping treatment due to adverse effects. The most common adverse events were tiredness, mood change and weight gain. CONCLUSION The data provide supportive evidence from tertiary headache practice in the UK for the use of flunarizine in migraine. The data encourages development of future guidance regarding flunarizine use in headache centres in countries where its use is not routine.
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Affiliation(s)
- N Karsan
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London.,NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
| | - D Palethorpe
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London.,NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
| | - W Rattanawong
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London.,NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
| | - J C Marin
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London.,NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
| | - R Bhola
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London.,NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
| | - P J Goadsby
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London.,NIHR-Wellcome Trust King's Clinical Research Facility, King's College Hospital, London, UK
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Ong JJY, De Felice M. Migraine Treatment: Current Acute Medications and Their Potential Mechanisms of Action. Neurotherapeutics 2018; 15:274-290. [PMID: 29235068 PMCID: PMC5935632 DOI: 10.1007/s13311-017-0592-1] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Migraine is a common and disabling primary headache disorder with a significant socioeconomic burden. The management of migraine is multifaceted and is generally dichotomized into acute and preventive strategies, with several treatment modalities. The aims of acute pharmacological treatment are to rapidly restore function with minimal recurrence, with the avoidance of side effects. The choice of pharmacological treatment is individualized, and is based on the consideration of the characteristics of the migraine attack, the patient's concomitant medical problems, and treatment preferences. Notwithstanding, a good understanding of the pharmacodynamic and pharmacokinetic properties of the various drug options is essential to guide therapy. The current approach and concepts relevant to the acute pharmacological treatment of migraine will be explored in this review.
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Affiliation(s)
- Jonathan Jia Yuan Ong
- Headache Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
- NIHR-Wellcome Trust King's Clinical Research Facility, Kings College Hospital, London, UK.
- Department of Medicine, Division of Neurology, National University Health System, University Medicine Cluster, Singapore, Singapore.
| | - Milena De Felice
- School of Clinical Dentistry, The University of Sheffield, Sheffield, UK
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Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy. Int J Mol Sci 2018; 19:ijms19020619. [PMID: 29470411 PMCID: PMC5855841 DOI: 10.3390/ijms19020619] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/15/2018] [Accepted: 02/18/2018] [Indexed: 02/01/2023] Open
Abstract
Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α₂δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.
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Indelicato E, Nachbauer W, Eigentler A, Donnemiller E, Wagner M, Unterberger I, Boesch S. Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment. Cephalalgia 2017; 38:1167-1176. [PMID: 28856914 DOI: 10.1177/0333102417715229] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9-15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term.
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Affiliation(s)
- Elisabetta Indelicato
- 1 Department of Neurology, Medical University Innsbruck, Anichstrasse, Innsbruck, Austria
| | - Wolfgang Nachbauer
- 1 Department of Neurology, Medical University Innsbruck, Anichstrasse, Innsbruck, Austria
| | - Andreas Eigentler
- 1 Department of Neurology, Medical University Innsbruck, Anichstrasse, Innsbruck, Austria
| | - Evelin Donnemiller
- 2 Department of Nuclear Medicine, 27280 Medical University Innsbruck , Anichstrasse, Innsbruck, Austria
| | - Michaela Wagner
- 3 Department of Neuroradiology, 27280 Medical University Innsbruck , Anichstrasse, Innsbruck, Austria
| | - Iris Unterberger
- 1 Department of Neurology, Medical University Innsbruck, Anichstrasse, Innsbruck, Austria
| | - Sylvia Boesch
- 1 Department of Neurology, Medical University Innsbruck, Anichstrasse, Innsbruck, Austria
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Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev 2017; 97:553-622. [PMID: 28179394 PMCID: PMC5539409 DOI: 10.1152/physrev.00034.2015] [Citation(s) in RCA: 1150] [Impact Index Per Article: 143.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.
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Affiliation(s)
- Peter J Goadsby
- Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and Department of Neurology, University Hospital Bern-Inselspital, University of Bern, Bern, Switzerland
| | - Philip R Holland
- Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and Department of Neurology, University Hospital Bern-Inselspital, University of Bern, Bern, Switzerland
| | - Margarida Martins-Oliveira
- Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and Department of Neurology, University Hospital Bern-Inselspital, University of Bern, Bern, Switzerland
| | - Jan Hoffmann
- Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and Department of Neurology, University Hospital Bern-Inselspital, University of Bern, Bern, Switzerland
| | - Christoph Schankin
- Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and Department of Neurology, University Hospital Bern-Inselspital, University of Bern, Bern, Switzerland
| | - Simon Akerman
- Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom; Department of Neurology, University of California, San Francisco, San Francisco, California; Department of Neurology, University of Hamburg-Eppendorf, Hamburg, Germany; and Department of Neurology, University Hospital Bern-Inselspital, University of Bern, Bern, Switzerland
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Sutherland HG, Griffiths LR. Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders. Headache 2017; 57:537-569. [PMID: 28271496 DOI: 10.1111/head.13053] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 01/09/2017] [Indexed: 12/20/2022]
Abstract
Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome-wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.
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Affiliation(s)
- Heidi G Sutherland
- Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, QUT, Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Lyn R Griffiths
- Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, QUT, Musk Ave, Kelvin Grove, QLD, 4059, Australia
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Camia F, Pisciotta L, Morana G, Schiaffino MC, Renna S, Carrera P, Ferrari M, Baglietto MG, Veneselli E, Siri L, Mancardi MM. Combined early treatment in hemiplegic attacks related to CACNA1A encephalopathy with brain oedema: Blocking the cascade? Cephalalgia 2016; 37:1202-1206. [PMID: 27651281 DOI: 10.1177/0333102416668655] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Introduction Variants in the CACNA1A gene on chromosome 19p13 result in a spectrum of neurological phenotypes ranging from familial or sporadic hemiplegic migraine to congenital or progressive encephalopathies. Patients with CACNA1A variants often show acute attacks with ataxia or hemiplegia till coma, sometimes related to unilateral brain oedema. No guidelines for the medical management of these attacks are available since treatment is empiric, and many cases do not respond to common antimigraine drugs. Case description We report on the emergency personalized treatment protocol used in an 11 year-old girl with CACNA1A-related encephalopathy for the management of acute attacks of headache, hemiconvulsions and hemiplegia with coma. Discussion Combined corticosteroid pulses and hypertonic solution led to a reduction in severity and duration of acute attacks when administered in the early stages, characterized by migraine, seizure, fever, vomiting and impairment of consciousness associated to hemispheric slowing on the EEG.
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Affiliation(s)
- Francesca Camia
- 1 Unit of Child Neuropsychiatry, Head-Neck and Neuroscience Department, Giannina Gaslini Institute, Genoa, Italy
| | - Livia Pisciotta
- 1 Unit of Child Neuropsychiatry, Head-Neck and Neuroscience Department, Giannina Gaslini Institute, Genoa, Italy
| | - Giovanni Morana
- 2 Neuroradiology Unit, Giannina Gaslini Institute, Genoa, Italy
| | | | - Salvatore Renna
- 4 First Aid and Emergency Department, Giannina Gaslini Institute, Genoa, Italy
| | - Paola Carrera
- 5 IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Unit of Genomics for Human Disease Diagnosis, Milan, Italy.,6 IRCCS San Raffaele Scientific Institute Laboratory of Clinical Molecular Biology, Milan, Italy
| | - Maurizio Ferrari
- 6 IRCCS San Raffaele Scientific Institute Laboratory of Clinical Molecular Biology, Milan, Italy.,7 Vita-Salute San Raffaele University, chair of Clinical Pathology, Milan, Italy
| | - Maria Giuseppina Baglietto
- 1 Unit of Child Neuropsychiatry, Head-Neck and Neuroscience Department, Giannina Gaslini Institute, Genoa, Italy
| | - Edvige Veneselli
- 1 Unit of Child Neuropsychiatry, Head-Neck and Neuroscience Department, Giannina Gaslini Institute, Genoa, Italy
| | - Laura Siri
- 8 "La Nostra Famiglia" Association, Scientific Institute E. Medea, Varazze-Savona, Italy
| | - Maria Margherita Mancardi
- 1 Unit of Child Neuropsychiatry, Head-Neck and Neuroscience Department, Giannina Gaslini Institute, Genoa, Italy
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McLendon LA, Kralik SF, Grayson PA, Golomb MR. The Controversial Second Impact Syndrome: A Review of the Literature. Pediatr Neurol 2016; 62:9-17. [PMID: 27421756 DOI: 10.1016/j.pediatrneurol.2016.03.009] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 03/11/2016] [Accepted: 03/18/2016] [Indexed: 01/13/2023]
Abstract
BACKGROUND Second impact syndrome is a devastating injury that primarily affects athletic children and young adults. It occurs when a second concussion occurs before symptoms from the first concussion have resolved. Diffuse and often catastrophic cerebral edema results. Reports of second impact syndrome are few, and some argue that second impact syndrome is simply diffuse cerebral swelling unrelated to the first concussion. METHODS Ovid and PubMed were searched from years 1946 to 2015 using the terms "second impact syndrome," "repeat concussion," and "catastrophic brain injury." In addition, review articles were found using a combination of the terms, "concussion," "second impact syndrome," and "repetitive head trauma." RESULTS Seventeen patients in seven publications met the criteria of having two witnessed hits and persistent symptoms from the first to the second concussion. Ten of the 17 (59%) included individuals were football players. All were male. Ages ranged from 13 to 23 years. All children with poor outcomes (death or permanent disability) were younger than 20 years, while four of the five players with good outcomes were older than 19 years. The lag time from first to second concussion ranged from one hour to four weeks, and in many cases, at least one of the two hits appeared minor. CONCLUSIONS American football, male gender, and young age appear to be associated with second impact syndrome. Controversies surrounding this syndrome are discussed. There is a need for prospective studies to clarify risk factors and outcomes of second impact syndrome to guide return-to-play recommendations for young athletes.
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Affiliation(s)
- Loren A McLendon
- Division of Pediatric Neurology, Department of Neurology, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana
| | - Stephen F Kralik
- Division of Pediatric Neuroradiology, Department of Radiology, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana
| | - Patricia A Grayson
- Division of Pediatric Neurology, Department of Neurology, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana
| | - Meredith R Golomb
- Division of Pediatric Neurology, Department of Neurology, Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana.
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Khodneva Y, Shalev A, Frank SJ, Carson AP, Safford MM. Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study. Diabetes Res Clin Pract 2016; 115:115-21. [PMID: 26818894 PMCID: PMC4887408 DOI: 10.1016/j.diabres.2016.01.021] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/02/2015] [Accepted: 01/10/2016] [Indexed: 11/26/2022]
Abstract
BACKGROUND Ca(2+) channel blockers (CCB) and verapamil in particular prevented β-cell apoptosis and enhanced endogenous insulin levels in recent studies of mouse models of diabetes. Verapamil's effect on serum glucose levels in humans with diabetes is not described. METHODS We used data from the REasons for Geographic and Racial Differences in Stroke (REGARDS), a national cohort study of community-dwelling middle-aged and older adults, enrolled between 2003 and 2007 from the continental United States. We examined associations of CCB and verapamil use with fasting serum glucose among 4978 adults with diabetes, controlling for covariates in generalized linear models (GLM). FINDINGS The sample included 1484 (29.6%) CCB users, of which 174 (3.4%) were verapamil users. In fully adjusted GLMs, CCB users had 5mg/dL lower serum glucose compared to non-users. Verapamil users had on average 10mg/dL lower serum glucose compared to CCB non-users with substantially greater differences among insulin users: 24mg/dL lower serum glucose among users of insulin in combination with oral agents and 37mg/dL lower among users of insulin alone. INTERPRETATION CCB and in particular verapamil use was associated with lower fasting blood glucose levels among REGARDS participants with diabetes. FUNDING UO1NS041588 from the National Institute of Neurological Disorders and Stroke, NIH; K24HL111154 and R01HL080477 from the National Heart, Lung, and Blood Institute.
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Affiliation(s)
- Yulia Khodneva
- Department of Medicine and Comprehensive Diabetes Center, School of Medicine, University of Alabama at Birmingham, Birmingham AL, United States.
| | - Anath Shalev
- Department of Medicine and Comprehensive Diabetes Center, School of Medicine, University of Alabama at Birmingham, Birmingham AL, United States
| | - Stuart J Frank
- Department of Medicine and Comprehensive Diabetes Center, School of Medicine, University of Alabama at Birmingham, Birmingham AL, United States
| | - April P Carson
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham AL, United States
| | - Monika M Safford
- Department of Medicine and Comprehensive Diabetes Center, School of Medicine, University of Alabama at Birmingham, Birmingham AL, United States
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50
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Mathew PG, Krel R, Buddhdev B, Ansari H, Joshi SG, Spinner WD, Klein BC. A retrospective analysis of triptan and dhe use for basilar and hemiplegic migraine. Headache 2016; 56:841-848. [PMID: 27062528 DOI: 10.1111/head.12804] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 01/10/2016] [Accepted: 01/10/2016] [Indexed: 01/03/2023]
Abstract
BACKGROUND Patients with basilar migraine (BM) and hemiplegic migraine (HM) have been excluded from triptan and DHE clinical trials due to a potential risk of ischemic vascular events, and the FDA mandates that package labeling state that they are contraindicated in BM and HM. The objective of this study was to demonstrate that triptans and DHE can be used for the abortive treatment of BM and HM without significant adverse ischemic vascular events. METHODS A retrospective chart review of patients with BM features or HM who received acute abortive treatment with either triptans or DHE was conducted at 4 headache centers to assess the frequency of ischemic vascular events after administration. The diagnoses of BM or HM were made by headache specialists based on The International Classification of Headache Disorders, 2nd edition (ICHD-II). Searchable terms included BM, vertigo, dysarthria, diplopia, hemiplegia/hemiparesis, facial droop, weakness, confusion, altered consciousness, confusion, ataxia, and aphasia, as well as all triptans or DHE. RESULTS The study included 67 patients with BM features and 13 patients with HM. Among those receiving triptans, 40 were in the BM group and 5 were in the HM group. Among those receiving DHE, 27 were included in the BM group and 8 were in the HM group. No side effects of stroke or myocardial infarction were reported. In the triptan group, 5 patients reported adverse effects that included GI upset, rash, neck dystonia, nightmares, and flushing. In the DHE group, 5 patients had adverse events that included chest tightness, dystonic reaction, transient asymptomatic anterior T wave inversion, and agitation. CONCLUSION In this retrospective study, triptans and DHE were used with no reported, subsequent acute/subacute ischemic vascular events for the abortive treatment of migraines with basilar and hemiplegic-type features. Although the small sample sizes generated theoretical statistical event rates of 4.5% for BM and 23% for HM, there has been no clear evidence that BM and HM carry an actual elevated risk for vascular events compared with migraine with aura.
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Affiliation(s)
- Paul G Mathew
- Department of Neurology, Brigham and Women's Hospital, John R. Graham Headache Center, Boston, MA, USA.,Department of Neurology, Harvard Vanguard Medical Associates, Braintree, MA, USA.,Division of Neurology, Cambridge Health Alliance, Cambridge, MA.,Harvard Medical School, Boston, MA, USA
| | - Regina Krel
- Department of Neurology, Brigham and Women's Hospital, John R. Graham Headache Center, Boston, MA, USA.,Department of Neurology, Harvard Vanguard Medical Associates, Braintree, MA, USA
| | - Bhuvin Buddhdev
- Division of Pulmonary, University of Nebraska Medical Center, Critical Care, Sleep & Allergy, Omaha, NE, USA
| | - Hossein Ansari
- Department of Neurology, University of California San Diego, San Diego, CA, USA
| | - Shivang G Joshi
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
| | | | - Brad C Klein
- Abington Headache Center, Abington Memorial Hospital, Abington, PA, USA.,Abington Neurological Associates, Willow Grove, PA, USA
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