Anne Christine Poole, General Practitioner and Headache Specialist, Oslo Headache Centre. 
This case study describes the challenges of counselling patients with migraine about the safety of treatment during pregnancy and while they are breast feeding.

Reference

1. Steiner TJ, Stovner LJ, Katsarava Z, et al. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain. 2014;15:31. doi: 10.1186/1129-2377-15-31.

Hans Christopher Diener, Professor of Neurology and Chairman of the Department of Neurology, University Duisberg-Essen, Germany. 
A 2019 review of the prevention and treatment of medication overuse headache recommended that treatment for migraine attacks should be withdrawn, eliminating the use of acute medication for 2–4 weeks, reducing the frequency of acute medication to less than 2 days per week and switching from triptans or combination analgesics to NSAIDs.1 This, in light of what is now known about the efficacy safety of the anti-CGRP monoclonal antibodies, is outdated advice.

References

1. Diener HC, Dodick D, Evers S, et al. Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol. 2019;18:891-902.
2. Silberstein SD, Cohen JM, Seminerio MJ, et al. The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study. J Headache Pain. 2020;21:114. doi: 10.1186/s10194-020-01173-8.
3. Silberstein SD, Kudrow D, Cohen JM, et al. Long-term impact of fremanezumab on response rate, acute headache medication use, and disability in episodic migraine patients with acute medication overuse at baseline: results of a 1-year study. Headache 2019;59 Suppl 1:113-114. Abstract P141.
4. Ferrari MD, Diener HC, Spierings EL, et al. Efficacy, clinically meaningful responses, and impact on acute headache medication use with fremanezumab in patients with migraine and documented inadequate response to 2–4 classes of migraine preventive treatments: results of the international, multicentre, randomised, placebo-controlled FOCUS study. J Headache Pain 2020;21:43. Abstract A.59.
5. Aurora SK, Ruff D, Pearlman EM. Medication overuse in a post-hoc analysis of Phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Headache 2019;59 Suppl S1:23. Abstract IOR07.
6. Tepper SJ, Diener HC, Ashina M, et al. Efficacy of erenumab for the treatment of patients with chronic migraine in presence of medication overuse. Cephalalgia 2017;37 Suppl 1: abstract EP-01-013.

Marja-Liisa Sumelahti, MD, PhD, Specialist in Neurology, Faculty of Medicine and Health Technology, Tampere University, Finland. 
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an hereditary angiopathy caused by mutations in the NOTCH3 gene. It is rare, with a prevalence of 5 per 100,000; it is associated with an increased risk of transient ischaemic attack, cognitive defects and migraine developing after age 45, and has a highly variable progressive clinical course.

Annelies Van Dycke, MD, PhD Neurologist, AZ Sint-Jan, Bruges, Belgium. 
The prevalence of epilepsy is 0.5—1.0% and that of migraine is 15—18% in women, 6% in men and 4% in children. Epidemiological studies show that comorbidity between these disorders is high, with migraine occurring in about 25% of people with epilepsy and epilepsy reported in 1—2% of people with migraine.1

Reference

1. Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 2006;5:148-157.

Rigmor Højland Jensen, Dr Med, Professor of Neurology, Director of Danish Headache Center. 
Medication overuse headache (MOH) presents a therapeutic challenge. It is relatively common, with an overall prevalence in the general population of 1—2% but up to 50% in specialised headache clinics, and the cost of management is three times greater than for migraine. It is associated with depression and anxiety, disability and impaired quality of life.1 However, although this challenge is recognised there is uncertainty about the best management strategy.

References

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204-1222.
2. Evers S, Jensen R; European Federation of Neurological Societies. Treatment of medication overuse headache — guideline of the EFNS headache panel. Eur J Neurol. 2011;18:1115-21.
3. Diener HC, Dodick D, Evers S, et al. Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol. 2019;18:891-902.
4. Carlsen LN, Munksgaard SB, Nielsen M, et al. Comparison of 3 treatment strategies for medication overuse headache: a randomized clinical trial. JAMA Neurol. 2020;77:1069-1078.
5. Carlsen LN, Munksgaard SB, Jensen RH, et al. Complete detoxification is the most effective treatment of medication-overuse headache: a randomized controlled open-label trial. Cephalalgia. 2018;38:225-236.
6. Engelstoft IMS, Carlsen LN, Munksgaard SB, et al. Complete withdrawal is the most feasible

Hashmat Ghanizada, MD and PhD Fellow, Danish Headache Center, Rigshospitalet, Glostrup, Denmark. 
CGRP is one of a family of peptides which share varying degrees of affinity with their receptors. Treatments to prevent migraine are not effective in all patients; this may be due to the effects of other calcitonin peptides in the trigeminal ganglion, including amylin and adrenomedullin.

References

1. Hay DL, Garelja ML, Poyner DR, Walker CS. Update on the pharmacology of calcitonin/ CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol. 2018;175:3-17.
2. Garelja ML, Au M, Brimble MA, et al. Molecular mechanisms of Class B GPCR activation: insights from adrenomedullin receptors. ACS Pharmacol Transl Sci. 2020;3:246-262.
3. Edvinsson L, Grell AS, Warfvinge K. Expression of the CGRP family of neuropeptides and their receptors in the trigeminal ganglion. J Mol Neurosci. 2020;70:930-944.
4. Walker CS, Eftekhari S, Bower RL, et al. A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. Ann Clin Transl Neurol. 2015;2:595-608.
5. Ashina M, Hansen JM, Á Dunga BO, et al. Human models of migraine - short-term pain for long-term gain. Nat Rev Neurol. 2017;13:713-724.
6. Charles A, Pozo-Rosich P. Targeting calcitonin generelated peptide: a new era in migraine therapy. Lancet. 2019;394:1765-1774.

Lars Edvinsson, MD, DMSci Professor, of Internal Medicine, Lund University, Lund, Sweden, and Copenhagen University, Denmark. 
CGRP appears to induce pain by modulating the activity of Aδ fibres at the nodes of Ranvier, where they occur in close proximity to C fibres. It is likely that CGRP induces cAMP and protein kinase A (PKA), resulting in inhibition/activation of K+ channels. This may offer a new therapeutic target for future migraine treatments.

References

1. Lundblad C, Haanes KA, Grände G, et al. Experimental inflammation following dural application of complete Freund's adjuvant or inflammatory soup does not alter brain and trigeminal microvascular passage. J Headache Pain. 2015;16:91. doi: 10.1186/ s10194-015-0575-8.
2. Haanes KA, Edvinsson L. Pathophysiological mechanisms in migraine and the identification of new therapeutic targets. CNS Drugs. 2019;33:525-537.
3. Zhang L, Kunkler PE, Knopp KL, et al. Role of intraganglionic transmission in the trigeminovascular pathway. Mol Pain. 2019;15:1744806919836570. doi: 10.1177/1744806919836570.
4. Melo-Carrillo A, Strassman AM, Nir RR, et al. Fremanezumab - A humanized monoclonal anti-CGRP antibody-inhibits thinly myelinated (Aδ) but not unmyelinated (C) meningeal nociceptors. J Neurosci. 2017;37:10587-10596.
5. Edvinsson JCA, Warfvinge K, Krause DN, et al. C-fibers may modulate adjacent Aδ-fibers through axon-axon CGRP signaling at nodes of Ranvier in the trigeminal system. J Headache Pain. 2019;20:105. doi: 10.1186/ s10194-019-1055-3.

Jan Versijpt, MD, PhD Neurologist, UZ Brussel, Belgium. 
Migraine management is not fully meeting the needs of patients and clinicians in three important areas: the role of monoclonal antibodies targeting CGRP, understanding the clinical role of neuromodulation and the development of biomarkers for migraine.

References

1. Alex A, Vaughn C, Rayhill M. Safety and tolerability of 3 CGRP monoclonal antibodies in practice: a retrospective cohort study. Headache. 2020;60:2454-2462.
2. Diener HC, Goadsby PJ, Ashina M, et al. Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial. Cephalalgia. 2019;39:1475-1487.
3. Durham P, Papapetropoulos S. Biomarkers associated with migraine and their potential role in migraine management. Headache. 2013;53:1262-77.
4. Cernuda-Morollón E, Larrosa D, Ramón C, et al. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81:1191-6.
5. Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers. Lancet Neurol. 2017;16:661-676.
6. Viana M, Sances G, Terrazzino S, et al. Predicting the response to a triptan in migraine using deep attack phenotyping: a feasibility study. Cephalalgia. 2020:333102420959786. doi: 10.1177/0333102420959786.