Chronic Migraine Out of Control Despite Multiple Drug Trials

CHALLENGING CASE

A 28-year-old woman comes to your clinic for preventive treatment of chronic migraines without aura. Her headaches started at age 16 and have progressively increased in frequency to about 6 to 10 headache days per month. She has not achieved migraine control despite adequate 8-week trials of several preventive drugs with established efficacy, including divalproex sodium, metoprolol, onabotulinumtoxinA, and frovatriptan.¹

History

Two months ago she started a trial of erenumab 70 mg once monthly. During the second month, the dose was increased to 140 mg once monthly when her symptoms failed to improve after the first injection. Despite tolerating the medication well, she still suffers from 6 to 10 migraine days per month.

She describes her headaches as a throbbing ache on her right forehead accompanied by photophobia, phonophobia, nausea, and occasional vomiting. Headaches last 7 to 10 hours and interfere with work and social activities. Triggers include stress and menstruation.

She is sexually active and currently uses birth control. She does not want to try valproate sodium or topiramate because of the risk of birth defects if she becomes pregnant.

She has no other significant medical problems and denies symptoms of depression or anxiety. Her family history includes migraines in her mother and sister.

She has read that the ketogenic diet may improve migraines and wants to know whether you would recommend a trial of it.

Examination

The patient’s body mass index is 25. Vital signs and the results of chest, cardiac, and abdominal examinations are normal. Neurological examination results are unchanged from the previous examination, without evidence of papilledema or focal neurological deficits.

Management

The American Headache Society recommends assessing outcomes after 3 months of therapy in patients who are receiving calcitonin gene-related peptide (CGRP) inhibitors that require monthly injections (erenumab and galcanezumab), and 6 months for CGRP inhibitors that require quarterly injections (fremanezumab).¹ Studies suggest that many patients who do not achieve at least 50% reduction in migraine headache days in the month after the first dose of a CGRP inhibitor may start to show a response after the second dose. A smaller proportion of patients may respond after the third dose,² and some individuals may start to respond after longer trials of up to 6 months.

In this case, the patient has had an inadequate trial of erenumab. Although she has been titrated up to the maximal dose, the duration of the trial is just 2 months. The patient is advised to continue with erenumab for at least one more month and return to clinic for assessment after the third month.

Details of the ketogenic diet are also discussed with her. After considering the pros and cons, she decides that a ketogenic diet would be too restrictive. She plans to wait one more month and will reconsider at her 3-month follow-up appointment.

Discussion

The ketogenic diet refers to a diet that is high in fat and low in carbohydrates. In the classic ketogenic diet, about 90% of calories come from fat with a 4:1 ratio of fat to protein plus carbohydrates. Other variants of the ketogenic diet include the medium chain triglyceride (MCT) diet, with 60% of energy from medium chain triglycerides, the modified Atkins diet (MAD) (a high-fat, low-carbohydrate diet similar to the classic ketogenic diet, but without a set ketogenic ratio), and the low glycemic index treatment (LGIT) diet, which emphasizes carbohydrates with low glycemic indices.

Currently, the ketogenic diet is recommended for treating refractory pediatric epilepsy, in combination with antiepileptic drugs.³ These recommendations are based on evidence that the ketogenic diet may decrease neuroexcitability, which may have implications for migraine control.

Interest in the ketogenic diet as a way to control migraine goes back at least to the turn of the 19th century.⁴ Since then, research on the topic has been relatively sparse. However, several case studies have suggested that ketosis may protect against migraine, and a 1-month small, observational study found significant reduction in migraine frequency, severity, and medication use associated with the ketogenic diet.⁵

Reasons for improvement are unclear, but a recent study suggests that a modified Atkins diet may decrease neuroexcitability in the cerebral cortex.⁶ The study included 22 participants with episodic migraine without aura. Researchers analyzed cortical evoked potentials in response to painful electric visual and somatosensory stimuli 1 month before and after starting a ketogenic diet. Results showed that ketosis was associated with normalization of neural response to pain, which may help in migraine prevention.

Other explanations have been proposed for how ketosis may improve migraine control. These include:
• Increased GABA (the main inhibitory neurotransmitter) and decreased glutamate (the main excitatory neurotransmitter)
• Decreased neuroinflammation
• Improved glycemic control associated with weight loss from the ketogenic diet

Still, whether or not the ketogenic diet benefits migraineurs remains an open question. Until larger, longer-term trials are conducted, the jury will remain out on the subject.

References:

1. American Headache Society. The American Headache Society Position Statement on Integrating New Migraine Treatments Into Clinical Practice. Headache. 2019;59:1-18. doi: 10.1111/head.13456.

2. Nichols R, Doty E, Sacco S, et al. Analysis of initial nonresponders to galcanezumab in patients with episodic or chronic migraine: results from the EVOLVE-1, EVOLVE-2, and REGAIN randomized, double-blind, placebo-controlled studies. Headache. 2019;59:192-204. doi: 10.1111/head.13443.

3. Kossoff EH, Zupec-Kania BA, Auvin S, et al, for the Practice Committee of the Child Neurology Society. Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018;3:175-192. doi: 10.1002/epi4.12225.

4. CJ Barbourka. Migraine results of treatment by ketogenic diet in fifty cases. JAMA. 1930;95:1825-1828. doi:10.1001/jama.1930.02720240035010.

5. Di Lorenzo C, Coppola G, Sirianni G, et al. Migraine improvement during short lasting ketogenesis: a proof-of-concept study. Eur J Neurol. 2015;22:170-177. doi: 10.1111/ene.12550.

6. Di Lorenzo C, Coppola G, Bracaglia M, et al. A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs. BMC Neurol. 2019;19:136. doi: 10.1186/s12883-019-1351-1.