Genetic migraine disorders and the response to calcitonin gene‐related peptide antagonist treatment

Abstract

Calcitonin gene‐related peptide (CGRP) is a potent cerebral vasodilator and part of the trigeminal migraine cascade. Newer migraine therapies target CGRP signaling for both acute and preventative management of headache. In this series, we present two cases of genetic conditions, of which migraine is a key feature, responsive to CGRP antagonist therapy. A 31‐year‐old female with mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes and a phenotype of chronic migraine with visual aura, and a 62‐year‐old female with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with a phenotype of chronic migraine and side‐locked headache with cranial autonomic symptoms. Each experienced a significant reduction in the frequency of their migraine attacks with monoclonal antibody treatment against CGRP. In this case series, we add to the growing body of evidence that CGRP‐blocking medications are safe and effective in some heritable neurological disorders in which vasomodulation is a common underlying pathology. To our knowledge, we present the first cases of galcanezumab use in an individual with mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes and eptinezumab in an individual with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Abbreviations

CADASIL

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CGRP

calcitonin gene‐related peptide

MELAS

mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes

p.o.

orally (per os)

PRN

as needed (pro re nata)

Migraine is a common neurological headache disorder caused by activation of the trigeminal vascular system. Elevated calcitonin gene‐related peptide (CGRP) levels have been detected in the saliva ¹ , ² and tears ³ of participants with chronic migraine both during and between acute attacks. As a result, the United States Food and Drug Administration has approved the use of generally well tolerated CGRP‐blocking medications for both acute and preventative management of migraine. Four monoclonal antibodies are approved for headache prevention (erenumab, fremanezumab, galcanezumab, and eptinezumab), while small‐molecule CGRP receptor antagonists include two therapies for prevention (atogepant, rimegepant) and three for acute management (ubrogepant, rimegepant, zavegepant). In the present case series, we present two patients with genetic disorders in which migraine is a key feature and their response to CGRP‐blocking therapy. Both patients provided written consent for their cases to be published.

A 31‐year‐old female with mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes (MELAS) was seen for headache consultation. She had never experienced seizures or stroke‐like episodes associated with her MELAS. She had a history of migraine headache since adolescence, described as bifrontal, throbbing, and associated with photophobia, phonophobia, and nausea. Preceding her headaches, she would often experience a visual aura. Her headaches would typically last hours and were worsened with routine activities. There were no associated focal neurological deficits or “red flag” features. Following the birth of her children, she had worsening of her headache frequency and intensity to the point where she was experiencing 1–2 headache‐free days/month and resulting in several presentations to the emergency department for status migrainosus. Within her family, there was a history of maternal migraine and MELAS. She was diagnosed with headache attributed to MELAS, meeting the third edition of the International Classification of Headache Disorders criteria for migraine with visual aura. Neurological examination and head computed tomography were unremarkable. She initially had a trial of ubrogepant 100 mg orally (p.o.) as needed (PRN) and almotriptan 12.5 mg p.o. PRN but this was ineffective in acutely managing her headaches. She found benefit with topiramate 50 mg p.o. daily as a preventative treatment, reducing her headache frequency to ~15–20 headache‐days/month. Given the consistent high frequency of her migraine, she had a trial of nadolol, which she did not tolerate. She subsequently started galcanezumab 120 mg/mL subcutaneously every month, and at her quarterly follow‐up she endorsed significant improvement to the point she experienced some months completely headache‐free. Over the last 2 years, she has continued to have quarterly follow‐up at the headache clinic.

A 62‐year‐old female with a previous right putamen stroke and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was seen for headache consultation at our centre. Her medical history included hypertension, dyslipidemia, pernicious anemia, Hashimoto's thyroiditis, anxiety, and depression. Her family history was significant for migraine in her maternal grandmother, stroke in her father, as well as a personal history of childhood migraine equivalents (motion sickness). Her migraine headaches began in adolescence and were described as severe pulsating and pressure associated with photophobia, phonophobia, and nausea with an average duration of 8–12 h. Again, there were no associated focal neurological deficits or “red flag” features; however, over the preceding 5 years, she experienced side‐locked left temporal headache and autonomic features including left tearing, facial sweating, and nasal discharge. She was subsequently diagnosed with chronic migraine and side‐locked headaches with cranial autonomic symptoms. On average, she experienced 8–10 headache‐free days/month. Her neurological examination and head computed tomography were unremarkable, aside from stable moderate supratentorial white matter hypoattenuation related to her CADASIL. She previously tried several preventative therapies for migraine without effect, including venlafaxine, topiramate, amitriptyline, erenumab, and onabotulinumtoxinA. A trial of fremanezumab 225 mg/1.5 mL subcutaneously for four cycles for prevention and acute management with ubrogepant 100 mg p.o. PRN were ineffective. She subsequently tried eptinezumab 100 mg/mL intravenously, which reduced her headache frequency to ~8–9 headache‐days/month when seen at her next follow‐up 3 months later. She has been followed by our headache clinic for the last 2 years and continues to have adequate migraine control.

Migraine is a common comorbid and key feature in several genetic neurological conditions. MELAS is a disease of abnormal mitochondrial metabolism with maternal inheritance. Common features of this disorder include stroke‐like episodes that do not respect vascular territories, epilepsy, migraine, and polyneuropathy, among others. CADASIL is one of the most common heritable causes of stroke and vascular dementia caused by a mutation in the NOTCH3 gene on chromosome 19. ⁴ Clinically, individuals with CADASIL often present with migraine, ⁴ recurrent ischemic strokes, and neuropsychiatric disturbances. ⁵ Management of migraine in these populations holds several barriers and concerns as many acute and preventative medications have potential vasomodulatory effects that can adversely impact the capillary endothelium or cause vasoconstriction, subsequently and potentially exacerbating the underlying disease. As such, clinicians may be hesitant to use CGRP‐blocking medications in these populations despite their safety. ⁶ Two groups similarly reported a significant reduction in migraine frequency and intensity of pain in patients with CADASIL with erenumab. ⁷ , ⁸ The efficacy of erenumab for migraine prevention was additionally reported by Naegel et al. in 2021. ⁹ Additionally, Silvestro et al. in 2023 ¹⁰ demonstrated improvement in headache frequency in individuals with other mitochondrial disorders including neuropathy, ataxia, and retinitis pigmentosa syndrome and progressive external ophthalmoplegia with galcanezumab.

To our knowledge, we present the first cases of galcanezumab use in an individual with MELAS and eptinezumab in an individual with CADASIL. In our experience, we found improvement of migraine frequency in these patients with the monoclonal antibody CGRP targeting‐blocking therapies, and neither experienced adverse side effects at 3 months follow‐up. These cases illustrate that there may be CGRP driven processes driving migraine even in those who have genetically determined migraine. Future studies are required with larger samples of patients of varying heritable neurological disorders to truly understand the efficacy and potential complications of these medications in these populations. In the interim, prescription of CGRP‐blocking therapies should be considered on an individual case basis after clear discussion with the patient and with clinical surveillance by a specialist.

AUTHOR CONTRIBUTIONS

Study concept and design: Andrea M. Kuczynski, William S. Kingston. Acquisition of data: Andrea M. Kuczynski, William S. Kingston. Analysis and interpretation of data: Andrea M. Kuczynski, William S. Kingston. Drafting of the manuscript: Andrea M. Kuczynski, William S. Kingston. Revising it for intellectual content: Andrea M. Kuczynski, William S. Kingston. Final approval of the completed manuscript: William S. Kingston.

CONFLICT OF INTEREST STATEMENT

Andrea M. Kuczynski and William S. Kingston have no conflicts of interest to declare.

Kuczynski AM, Kingston WS. Genetic migraine disorders and the response to calcitonin gene‐related peptide antagonist treatment. Headache. 2025;65:1041‐1043. doi: 10.1111/head.14942