COMMENTARY

Post–COVID-19 Headache and Migraine: What's the Connection?

Deena E. Kuruvilla, MD

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March 11, 2022

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This transcript has been edited for clarity.

My name is Deena Kuruvilla. I am a neurologist, a headache specialist, and the medical director of the Westport Headache Institute. I am going to be talking to you today about post–COVID-19 headache and its very complicated relationship with migraine.

We know that since this pandemic started, we have seen so many different neurologic manifestations of SARS-CoV-2. It's been baffling to me as a clinical provider who's worked in the hospital and in the outpatient clinic to see the variety of neurologic manifestations. I've seen everything from headache to dizziness, to loss of smell (anosmia), to changes in taste (ageusia), stroke, encephalopathy, seizure, and Guillain-Barré syndrome. There's been such a potpourri of different variations of neurologic illnesses that we've seen, but I would definitely have to say that headache is by far one of the most common neurologic manifestations of the disease.

As an outpatient physician, patients often follow up with me once they have had the infection and have presented with headache, and I'm usually asked to manage their outpatient headache care. I would have to say that there has been such a broad prevalence of headache after COVID-19. The literature has quoted that anywhere from 6% to around 70% of patients with COVID-19 experience headache. There's been such a high prevalence of folks that we've seen with this particular manifestation.

Most of the studies that have been done have basically shown that the most common phenotype that we see with post–COVID-19 headache is migraine. Many of these patients who come to my clinic tell me that they are experiencing a unilateral or side-switching, throbbing headache or dull headache associated with characteristic migraine features like sensitivity to light, sensitivity to loud noise, nausea, vomiting, and worsening on exertion. I've certainly seen people with post–COVID-19 headache who have that phenotype of migraine respond to migraine-specific treatments as well.

It's a complicated story about post–COVID-19 headache, but once you pin down that phenotype of what the patient is experiencing with post–COVID-19 headache, it makes their evaluation and treatment much easier.

One question that I often get asked is, "How are we seeing this infection invade the central nervous system and produce headache?" There are so many different proposed mechanisms out there, but we do know that the SARS-CoV-2 spike protein specifically binds to the angiotensin-converting enzyme 2 receptors throughout the central nervous system. That's one of the key mechanisms that's been studied, as it mediates the neurologic manifestations that we end up seeing with the disease.

There are a number of other reasons that we may end up seeing headache as a manifestation of the virus, just as we see with other viruses, like enterovirus, influenza, etc. Other causes of headache in this population could be hypoxia, dehydration, systemic inflammation, and metabolic disturbances — that toxic metabolic cause for the headache, such as electrolyte imbalance. A host of different causes may be responsible for headache secondary to the SARS-CoV-2 infection.

What's really interesting is that research has shown that the cytokine storm [an accentuated immune response to triggers such as viruses] is activated as a result of the SARS-CoV-2 infection. The cytokine storm that ensues does cause the systemic inflammation, one of the main causes of headache in SARS-CoV-2. In addition to this systemic inflammation that we end up seeing as a result of the cytokine storm, calcitonin gene-related peptide (CGRP) release is one of the key factors that we know causes migraine.

CGRP has been studied since approximately 1993 as one of the key mechanisms that causes migraine. Now we know that with COVID-19, we see a very similar systemic inflammation. That is one of the key causes and one of the key targets that perhaps can be researched moving forward. [Studies show that elevated levels of the cytokine interleukin-6 may correlate with increased severity of COVID-19 illness. Because CGRP is known to enhance interleukin-6 production, migraine medications that block CGRP pathways are being investigated as a means of treatment.]

In addition to all of the mechanisms that we've been seeing, I've personally found it most helpful for these patients that we see with headache as one of their manifestations of COVID-19 to investigate for secondary causes for headache before determining a treatment regimen.

When I was working in the hospital setting, for many of the patients who came in with headache as a result of their COVID-19 disease, we pursued MRI of the brain with and without gadolinium in specific cases. In some cases, for more urgent evaluation, we may have done a CT scan or a CTA (CT angiography) of the head and the neck.

In some cases, we certainly did a lumbar puncture, as we do many times with patients coming in with headache as a manifestation of the virus. In these instances, we perform a viral panel of the cerebrospinal fluid, looking for bacterial causes, fungal causes, or other nonspecific inflammatory causes for that headache with which patients might be presenting.

The literature so far has shown that among patients who presented with headache as a manifestation of COVID-19, around 46% [47.1%] presented in the acute phase of illness. They really experienced that headache early on, usually within the first few days and certainly less than 30 days from when they were diagnosed with COVID-19.

Those rates do tend to drop over time. Around the 60-day mark, about 10% [16.5%] of people complained of headache, and that percentage remained about the same until the 90- to 180-day mark [10.6% at 90 days; 8.4% at 180 days]. After that, the incidence of headache as a manifestation of COVID-19 actually decreases.

It's really pertinent in the acute phase of illness to rule out those secondary causes for headache when patients are presenting initially with headache. Once those secondary causes are ruled out, then it's appropriate to figure out which phenotype the patient is experiencing as a result of this headache. Is it a classic migraine (migraine with aura) phenotype? Is it tension-type headache? Is it cluster headache? Is it hemicrania continua? Figuring out that phenotype is going to guide the specific treatment to which that patient responds. That's a big part of pursuing that workup and treatment for the patient.

A frequent question that I'm asked is whether post–COVID-19 headache worsens headache disease in people who already had a history of migraine. In a case-control study that investigated this, 57 people with a history of migraine and 144 without a history of migraine were interviewed 7.3 months after recovery from SARS-CoV-2. Results showed that when comparing the two groups, they did not find a difference in headache prevalence between them. The baseline migraine disease or headache, in general, did not worsen in the people who had a history of migraine compared with those without a history of migraine. Interestingly, though, in that study they did find that post–COVID-19 long-haul symptoms, such as fatigue, were more prevalent in people who had a history of migraine than in those who did not have a history of migraine.

I have to say that although the evidence does show that, in my clinic I honestly have seen an opposing view. In my clinic, in people who had a history of migraine, typically folks who had episodic migraine (experiencing fewer than 15 headache-days a month), I have found that having COVID-19 pushed them over the edge and put them into chronic migraine territory.

Patients with a history of migraine in my clinic — I've seen them experience a higher frequency and severity of headaches after having SARS-CoV-2 infection. Certainly, the research shows one thing and my clinical experience is a little bit different.

When I'm treating these patients in my clinic, in the outpatient setting long term, I do find that, especially in those patients who have a migraine phenotype, using a preventive migraine treatment coupled with an acute migraine treatment is a recipe that works well for them.

Small case studies have looked at what is the most common headache phenotype that we see in patients with post–COVID-19 headache, and migraine is typically the most common phenotype that's been shown in research. In my clinic, I have to say I've found the same thing. Migraine is the most common type of headache that I see in people who have post–COVID-19 headache. I've seen that these patients, once we've ruled out all of those dangerous causes for headache, respond beautifully to preventive and acute migraine treatments.

These patients are really important to identify in our individual practices because we can make a huge difference in their quality of life just by initiating that appropriate treatment regimen with a preventive treatment and acute treatment.

In my clinics, I do sometimes recommend integrative treatments for these patients as well, and some more natural approaches, such as mindfulness, meditation, acupuncture, nutraceuticals, and vitamins such as magnesium and riboflavin. Coupling these different treatment approaches and individualizing patient treatments in my clinic, I found, has been the best recipe for really helping these patients.

In conclusion, headache is the most common neurologic symptom that we see in patients with COVID-19. It may be a presenting symptom in this population. Migraine is the most common phenotype that we see in patients with post–COVID-19 headaches. It's important to rule out secondary causes for headache in these patients who are coming in with post–COVID-19 headache. Once dangerous causes for headache have been ruled out, I would really approach these patients with treatments specific to their headache phenotype.

Thank you so much for having me today.

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