Nordic Migraine Symposium 2020: Recent Episodes

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Louise Ninett Carlse‪n‬.
Three strategies are effective in reducing headache days in patients with MOH. These were compared in a non-blinded randomized trial in 120 patients with MOH associated with migraine or tensiontype headache: withdrawal plus preventive therapy from the outset, preventive therapy alone with no advice on withdrawal, and withdrawal alone (with an option to start preventive therapy after two months).6

References:

  1. Hagen K, Albretsen C, Vilming ST, et al. Management of medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia. 2009;29:221-32.
  2. Silberstein SD, Blumenfeld AM, Cady RK, et al. Onabotulinum toxin A for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. 2013;331:48-56.
  3. Tepper SJ, Diener HC, Ashina M, et al. Erenumab in chronic migraine with medication overuse: Subgroup analysis of a randomized trial. Neurology. 2019;92):e2309-e2320.
  4. Tassorelli C, Jensen R, Allena M, et al; the COMOESTAS Consortium. A consensus protocol for the management of medication-overuse headache: Evaluation in a multicentric, multinational study. Cephalalgia. 2014;34:645-655.
  5. Pijpers JA, Kies DA, Louter MA, et al. Acute withdrawal and botulinum toxin A in chronic migraine with medication overuse: a double-blind randomized controlled trial. Brain. 2019;142:1203-1214.
  6. 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.

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Lars Bendtsen MD, PhD, Associate Professor, Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup, University of Copenhagen, Denmark.
Sweden, Denmark, Norway and Finland have independently developed their regulations for reimbursing treatment with anti-CGRP monoclonal antibodies, resulting in different levels of access to treatment and inconsistent eligibility criteria.

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Lars Jacob Stovner MD, PhD, Professor of Neurology, Norwegian University of Science and Technology and Norwegian Advisory Unit on Headaches, St. Olavs Hospital, Trondheim, Norway.
Sweden, Denmark, Norway and Finland have independently developed their regulations for reimbursing treatment with anti-CGRP monoclonal antibodies, resulting in different levels of access to treatment and inconsistent eligibility criteria.

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Signe Bruun Munksgaar‪d‬. 
The European Academy of Neurology guideline on the management of medication overuse headache (MOH) updates the 2011 guideline from the European Federation of Neurological Societies with new research and new diagnostic criteria.

Reference;

  1. Eur J Neurol. 2020 Jul;27(7):1102-1116. doi: 10.1111/ene.14268. Epub 2020 May 19

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Marja-Liisa Sumelahti MD, PhD, Specialist in Neurology, Faculty of Medicine and Health Technology, Tampere University, Finland.
Sweden, Denmark, Norway and Finland have independently developed their regulations for reimbursing treatment with anti-CGRP monoclonal antibodies, resulting in different levels of access to treatment and inconsistent eligibility criteria.

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Ingela Nilsson Remahl MD, PhD, Head of the Headache Center, Karolinska University Hospital.
Sweden, Denmark, Norway and Finland have independently developed their regulations for reimbursing treatment with anti-CGRP monoclonal antibodies, resulting in different levels of access to treatment and inconsistent eligibility criteria.

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Gürdal Sahin, MD, PhD, Specialist in Neurology and Head of the Skåneuro Private Headache and Movement Disorders Clinic, Institution for Clinical Sciences, Lund University.
Social distancing during the Covid pandemic has limited clinicians’ ability to provide face-to-face care and disrupted the assessment, monitoring and supervision normally provided in outpatient clinics. Telemedicine is an option for providing care remotely that offers service continuity, with some success in the management of headache.1-3 Its uptake during the pandemic may foretell a wider role in the future (Figure 1).

References

  1. Friedman DI, Rajan B, Seidmann A. A randomized trial of telemedicine for migraine management. Cephalalgia. 2019;39:1577-1585.
  2. Müller KI, Alstadhaug KB, Bekkelund SI. Acceptability, feasibility, and cost of telemedicine for nonacute headaches: a randomized study comparing video and traditional consultations. J Med Internet Res. 2016;18:e140. doi: 10.2196/jmir.5221.
  3. Müller KI, Alstadhaug KB, Bekkelund SI. Telemedicine in the management of non-acute headaches: a prospective, open-labelled non-inferiority, randomised clinical trial. Cephalalgia. 2017;37:855-863.
  4. Landsness EC, Wang LH, Bucelli RC. Ziprasidone as a potential abortive therapy for status migrainosus. Neurohospitalist. 2016;6:151-156.
  5. Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine prevention: evidence review and clinical implications. Cephalalgia. 2019;39:445-458.
  6. Robblee J, Starling AJ, Halker Singh RB et al. Teleneurology for primary headache disorders. Practical Neurology 2020;June:31-9.

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Marja-Liisa Sumelahti, MD, PhD, Specialist in Neurology, Faculty of Medicine and Health Technology, Tampere University, Finland.
There has been concern during the Covid pandemic that the immunosuppressive effects of medicines may increase the risk of infection. Little is known about the effect of migraine preventive medication on immune function but laboratory evidence of immunosuppression has not been reflected in clinical practice. Despite theoretical concerns, CGRP antagonists may confer some degree of protection against the complications of Covid.

References

  1. Sumelahti ML, Sumanen M, Sumanen MS, et al. My Migraine Voice survey: disease impact on healthcare resource utilization, personal and working life in Finland. J Headache Pain. 2020;21:118. doi: 10.1186/ s10194-020-01185-4.
  2. Zaccara G, Giovannelli F, Giorgi FS, et al. Do antiepileptic drugs increase the risk of infectious diseases? A meta-analysis of placebo-controlled studies. Br J Clin Pharmacol. 2017;83:1873-1879.
  3. Maier IL, Karch A, Mikolajczyk R, et al. Effect of betablocker therapy on the risk of infections and death after acute stroke—a historical cohort study. PLoS One. 2015 Feb 2;10(2):e0116836. doi: 10.1371/ journal.pone.0116836.
  4. Szałach ŁP, Lisowska KA, Cubała WJ. The influence of antidepressants on the immune system. Arch Immunol Ther Exp (Warsz). 2019;67:143-151.
  5. Ahmed F, Gaul C, García-Moncó JC, et al; REPOSE Principal Investigators. An open-label prospective study of the real-life use of onabotulinumtoxinA for the treatment of chronic migraine: the REPOSE study. J Headache Pain. 2019;20:26. doi: 10.1186/ s10194-019-0976-1.
  6. Hess DC, Eldahshan W, Rutkowski E. COVID-19-related stroke. Transl Stroke Res. 2020;11:322-325.
  7. American College of Cardiology, American Heart Association, Heart Failure Society of America. HFSA/ ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19, https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsaacc-aha-statement-addresses-concerns-re-using-raasantagonists-in-covid-19; accessed December 2020.
  8. Skaria T, Mitchell KJ, Vogel O, et al. Blood pressure normalization-independent cardioprotective effects of endogenous, physical activity-induced αCGRP (α Calcitonin Gene-Related Peptide) in chronically hypertensive mice. Circ Res. 2019;125:1124-1140.
  9. Mulder IA, Li M, de Vries T, et al. Anti-migraine calcitonin gene-related peptide receptor antagonists worsen cerebral ischemic outcome in mice. Ann Neurol. 2020;88:771-784.
  10. Biohaven Pharmaceuticals. Biohaven Receives FDA May Proceed Letter to Begin Phase 2 Trial of Intranasal Vazegepant to Treat Lung Inflammation After COVID-19 Infection. 9 April 2020. https://www.biohavenpharma.com/investors/news-events/pressreleases/ 04-09-2020.; accessed December 2020.
  11. Han L, Liu Y, Xiong H, et al. CGRP monoclonal antibody for preventive treatment of chronic migraine: an update of meta-analysis. Brain Behav. 2019;9:e01215. doi: 10.1002/brb3.1215.
  12. Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine prevention: Evidence review and clinical implications. Cephalalgia. 2019;39:445-458.
  13. Levin M, Silberstein SD, Gilbert R, et al. Basic considerations for the use of monoclonal antibodies in migraine. Headache. 2018;58:1689-1696.

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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.

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Mattias Linde, MD, PhD, Professor of Neurology, Norwegian Advisory Unit for Headaches and NTNU Consultant Neurologist, Tjörn Headache Clinic.
The group of people most highly burdened by migraine are women of childbearing age, with about 1 in 5 of 30- to 39-year-olds affected.1 The challenge of treatment and prevention during pregnancy and while breast feeding is therefore a frequent one. Fortunately, the frequency of migraine attacks declines towards the time of delivery; however, there is often a marked increase during the puerperium.2

References

  1. Linde M, Stovner LJ, Zwart JA, et al. Time trends in the prevalence of headache disorders. The Nord-Trondelag Health Studies (HUNT 2 and HUNT 3). Cephalalgia. 2011;31:585-96.
  2. Kvisvik EV, Stovner LJ, Helde G, et al. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;12:443-51.
  3. Steiner TJ, Jensen R, Katsarava Z, et al. Aids to management of headache disorders in primary care (2nd edition): on behalf of the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. J Headache Pain. 2019;20:57. doi: 10.1186/s10194-018-0899-2.
  4. Varkey E, Cider A, Carlsson J, et al. Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls. Cephalalgia. 2011;31:1428-38.
  5. Varkey E, Hagen K, Zwart JA, et al. Physical activity and headache: results from the Nord-Trøndelag Health Study (HUNT). Cephalalgia. 2008;28:1292-7.

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Eili Tranheim Kase, PhD, Associate Professor, Department of Pharmacy, University of Oslo.
Anti-CGRP monoclonal antibodies probably cross the placenta but there is no evidence of harm in humans as a result; levels in breast milk are very low, especially after one week. There are no data on human exposure to gepants during pregnancy but animal studies at doses comparable with clinical doses suggest any risk is low.

References

  1. Pham-Huy A, Sadarangani M, Huang V, et al. From mother to baby: antenatal exposure to monoclonal antibody biologics. Expert Rev Clin Immunol. 2019;15:221-229.
  2. Gisbert JP, Chaparro M. Safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during pregnancy: a review. Drugs. 2020l;80:1085-1100.
  3. Bussiere JL, Davies R, Dean C, et al. Nonclinical safety evaluation of erenumab, a CGRP receptor inhibitor for the prevention of migraine. Regul Toxicol Pharmacol. 2019;106:224-238.
  4. Cohen-Barak O, Weiss S, Rasamoelisolo M, et al. A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects. Cephalalgia. 2018;38:1960-1971.
  5. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain. 2019;20:37. doi: 10.1186/s10194-019-0974-3.
  6. de Vries T, Villalón CM, MaassenVanDenBrink A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther. 2020;211:107528. doi: 10.1016/j. pharmthera.2020.107528.
  7. Palmeira P, Quinello C, Silveira-Lessa AL, et al. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:985646. doi: 10.1155/2012/985646.

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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

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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.

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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.

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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.

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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.

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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.

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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.