James A. Charles, MD, FAAN, FAHS

Numerous articles emphasize the weak evidence and lack of efficacy of migraine preventatives that are recommended in the American Academy of Neurology (AAN) guidelines for pediatric migraine. In the 15 studies included in the literature review, there is not sufficient evidence to show that preventive treatments, such as divalproex, onabotulinumtoxinA, amitriptyline, nimodipine, and cinnarizine are more effective than placebo at reducing the frequency of headaches in this population. There is some evidence to show propranolol in children and cognitive behavioral therapy combined with amitriptyline, topiramate, and cinnarizine in children and adolescents can reduce headache frequency; however, cinnarizine is not available in the United States, topiramate may cause cognitive dysfunction, and beta-blockers cannot be given to those with asthma, which is highly comorbid with migraine, and they are not well-tolerated by athletes.

What happens to the approximate 24% of children and adolescents who don’t respond the to the AAN guideline for migraine preventatives?

Decreased areas of gray matter develop in several brain regions involved in pain processing: the right superior temporal gyrus; right transverse temporal gyrus; right parietal operculum; right inferior frontal gyrus; and left precentral gyrus. Chronic migraine patients have significantly more gray matter reductions in the left and right anterior cingulate; left amygdala; left parietal operculum; left middle, left inferior, and right inferior frontal gyrus; and left and right insular lobe than episodic migraine (EM) patients.

Reduced gray matter density in the brains of migraineurs becomes apparent, particularly in the cortex of the frontal and temporal lobes bilaterally. The decreased gray matter density is strongly associated with age, disease duration, and T2-visible lesion load. Patients with EM have significant reductions in gray matter volume in several regions of the brain: bilateral insula, bilateral motor/premotor cortex, bilateral prefrontal cortex, left dorsal anterior cingulate cortex, right dorsal posterior cingulate cortex, right inferior and superior parietal cortex, orbitofrontal cortex, and visual cortex. Progressive decreases in gray matter volume are noted with increasing migraine attack duration and increasing attack frequency, suggesting that repeated migraine attacks may produce atrophic changes in the pain processing regions of the brain.

Research shows the periaqueductal gray matter exhibits increased tissue iron levels in patients with chronic daily headache (CDH) and EM compared with controls, and the accumulation of iron correlates positively with the duration of illness. No differences in iron concentrations were detected between migraine with and without aura. These investigators also speculated that the increased R

 values in the EM and CDH groups indicated impaired iron homeostasis related to neuronal damage or dysfunction caused by repeated headache attacks.

Ineffective or no pharmacologic interventions will increase headache frequency and raise the risk of progression to chronic migraine.

How can we treat these headache-disabled children and adolescents that do not respond to the treatments outlined in the AAN preventive medicine guidelines?

Amy, age 15, began experiencing 3 headache days per month at age 4, 50% associated with visual aura. Frequency increased to 12 headache days per month over the past 10 months. Mother has migraine with aura. There are no medical or psychiatric comorbidities. She had failed adequate trials of topiramate, propranolol, and amitriptyline given by other neurologists. She required numerous rescue visits to emergency rooms. She lost many days of school placing her in academic jeopardy. Her last neurologist placed her on divalproex monotherapy several days prior to her presenting to my practice very unwell. We immediately treated her in our outpatient infusion center for 3 days with repetitive dihydroergotamine (DHE) and prochlorperazine and IV divalproex and SPG block under fluoroscopy. She was discharged on oral divalproex prevention with marked reduction of headache frequency and intensity. Abortive therapy was modestly effective with DHE IN and diclofenac buffered solution. She failed all previous triptans. Two weeks later, she relapsed and was retreated with a repeat 3 days of repetitive DHE and prochlorperazine and was started on oral memantine prophylaxis. Effective remission was again established and discharged on oral memantine prophylaxis. One week later, she again relapsed and when it became apparent her prognosis with recurrent episodic status migrainosis was becoming dismal, she was treated with a 3 days DHE/Prochlorperazine protocol and started on olanzapine 5 mg every 12 hours and given several follow-up outpatient SPG blocks under fluoroscopy. Amy’s headache frequency dropped to 2 headache days per month with satisfactory results from DHE IN and diclofenac buffered solution abortive therapy.

Six months later, now age 16, Amy stopped all of her medications citing fatigue, inability to lose weight, and difficulty with concentration. She was brought into the office where she was given erenumab 140 mg sample and was provided with a second sample the next month. Amy became headache free, off all preventatives except for monthly erenumab after the first dose and remained headache free for 5 months. She became the first teenager in New Jersey to obtain coverage for a calcitonin gene-related peptide (CGRP) monoclonal antibody.

CGRP mAbs were not studied in young populations under 18 years old. However, systemic exposure and clearance of drugs are generally similar in adolescents (ages 12-17) and adult patients after accounting for the effect of body size on pharmacokinetics.

 Double-blind, placebo-controlled trials of CGRP mAbs in children are years away. Growing numbers of parents who have migraine successfully treated with CGRP mAbs with no side effects are most likely not going to allow their children with debilitating migraine to be placed in the placebo arm of a paid trial. Like Amy, many of these children have failed conventional oral, spray, and injectable abortive, rescue, and preventive agents making the precipitous reduction in headache disability from CGRP mAbs unlikely to be a placebo effect which is a problem in placebo-controlled trials in children.

Erenumab (Aimovig; Amgen) has been studied for over 5 years in open-label extension (OLE) trials. Other CGRP mAbs are also beginning to publish OLE trials. No one has developed cancer, organ damage,  learning disability, or death. Constipation is at 1% to 3% and mostly manageable with diet changes. Real world injection site reactions are rare and manageable. To date, 250,000 patients are on erenumab. At 4.5 years, 80% of patients have had a sustained 50% reduction of headache days.

 are academically correct in their position that since the CGRP mAbs were not studied in children, a recommendation for their use cannot be published, but broadcasting this position can be harmful for the potential future coverage of CGRP mAbs by insurance providers for this population when all other preventives fail. I have experienced multiple cases of parents sharing their prescribed CGRP mAbs with their debilitated children or fronting the cost of the drugs themselves so their children can be successfully treated. Headache specialists know that many headache naïve patients will respond to the AAN guideline drugs like topiramate, propranolol, and CBT/amitriptyline and will prescribe them first-line; however, all headache specialists who treat children need to come together to send a unified message to health insurance providers that when children like Amy fail 2 or more AAN preventatives, insurance must authorize and reimburse the use of CGRP mAbs to prevent headache disability, keep them out the emergency department, stop them from losing time in school, and prevent them from converting into chronic and refractory CM as adults. Early, appropriate, and optimal treatment of migraine during childhood and adolescence may result in disease modi&#64257;cation and prevent progression of this disease, which is ranked as one of the most disabling diseases in the world.

This editorial was submitted by James A. Charles, MD, FAAN, FAHS, Director, Headache Treatment Program at Holy Name Medical Center in Teaneck, NJ  and Clinical Associate Professor of Neurology, Rutgers NJ Medical School.

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