Nina Riggins, MD, PhD

 infection occurs very frequently, and more studies are needed to better understand the pathophysiology of these headaches and to determine the best treatment options during the period of long COVID-19 syndrome. 

All clinicians who seek to “connect the dots” for the right diagnosis and the proper treatment of complex medical issues are recognizing the importance of carefully listening to the patient. A thorough medical history and physical examination provide critical information to neurologists, information that cannot be obtained simply by using modern technology. Collecting excellent history helps us to create an individualized treatment plan based on evidence-based medicine. As neurologists, we study the brain and believe in the powers of the brain. And despite the pandemic, a surge of important new research is emerging, as are new therapeutic developments in our field of medicine. 

I am a headache neurologist, and I have found that many patients report “migraine-like” headache, “tension-like” headache, and “trigeminal autonomic cephalalgia–like” headache in different time frames after they have tested positive for COVID-19. 

International Classification of Headache Disorders, Third Edition

), there is a definition for “headache attributed to systemic viral infection.”

 There is also the possibility that the cytokine storm–induced inflammation that occurs in many COVID-19 infections could be viewed in the ICHD-3 classifications as “headache attributed to other noninfectious inflammatory intracranial disease.”

 As the neurological impairments frequently seen in post–COVID-19 patients can have different pathophysiological bases— ranging from direct neurotoxicity to the consequences of hypoxia, hypertension, coagulopathy, and inflammation— multiple physiological factors might be leading to headache during and after the infectious period.

Headache appears to be a heterogenous entity in the setting of COVID19. Publications vary in their documentation of the percentage of people who report headache during acute COVID-19 infection, with numbers ranging from 14% to 60%, and these numbers might represent an underreporting of headache.

In addition to headache, patients with COVID-19 infections can have other neurologic manifestations. These can be both central nervous system–related (eg, dizziness, cerebrovascular disease, seizure, altered consciousness) or peripheral nervous system–related (eg, neuropathic pain). Skeletal muscular injury has also been reported.

Headache can be one of the prominent symptoms of COVID-19 infection. Results of some studies indicate that it is the most frequent first symptom of COVID-19. In 1 published report, headache persisted after 1 month in 13% of patients.4 In another study, one-third of followed-up patients had persistent disabling daily headache after 6 weeks, with poor response to acute treatment, and in more than 30% of patients, headache represented the only residual symptom following COVID-19 infection.

In short, a population of patients who have been infected with the virus suffer daily headache without any other symptoms. They may represent a group of new daily persistent headache patients who present at a neurology clinic weeks or even months after their bout with COVID-19, and only with a thorough medical history can it be determined that onset of headache was indeed in a setting of COVID-19 infection. 

It has been widely reported that a common symptom of COVID-19 infection is loss of the sense of smell, and a number of studies have examined the possible mechanism for this anosmia. The receptor for the virus, angiotensin converting enzyme-2, is present in the endothelium of blood vessels, including small vessels of the cerebral circulation and the meningeal endothelium.

 Some data suggest that patients with COVID-19 and headache vs those without headache are more likely to have anosmia.

One reason for loss of smell could be COVID-19–induced olfactory epithelial cell damage. Brain imaging in a patient with COVID-19 and anosmia demonstrated hyperintensity in the gyrus rectus and olfactory bulb areas of the brain.

 Following viral infection, an inflammatory response in the mucosa of the nose may be likely to occur. Also, activated trigeminal afferents would release calcitonin gene-related peptide. COVID-19 has been shown to activate the trigeminovascular system, and if sensitization of the trigeminovascular system continues, it can lead to persistent headache long after the first positive COVID-19 test.

 Thus, taken together, all these actions could lead to both headache and suppression of olfactory functions. 

We are just beginning to get a better understanding of long COVID syndrome. For example, it has been reported that COVID-19 disease severity might not be a good predictor of the onset of long COVID syndrome. Recognized symptoms of long COVID include fatigue and dyspnea, sleep changes, gastrointestinal (GI) symptoms, and dysautonomia; these can last for months after an acute COVID infection. Other persistent symptoms may include cognitive changes, generalized pain, and cardiac issues. 

Among the reported risk factors for long COVID are being female and displaying several specific early symptoms during COVID-19 infection.

 In addition, some evidence indicates that early dyspnea, prior psychiatric disorders, and specific biomarkers (eg, D-dimer, C-reactive protein, and lymphocyte count) put a patient at greater risk for developing long COVID.

 The gut-brain axis change has also been implicated as a potential contributor to the development of long COVID. Persistent gut dysbiosis brought on by COVID-19 infection could negatively modulate neurotransmitter circuitries in both the gut and the brain, and it may contribute to the neurologic symptoms of long COVID.

 This is another excellent example of how neurologists working as team members—in this case, with GI specialists and primary care clinicians—can provide the most helpful care to sufferers of long COVID. 

For patients who have been hospitalized with COVID-19 infections, the risk of experiencing residual symptoms can be high. Results of 1 study noted that the median proportion of individuals previously hospitalized with COVID-19 who were experiencing at least 1 persistent symptom after discharge was 72.5%.

Despite an abundance of literature and observations on the presence of headache after COVID-19 infection, not many results about evidence-based treatments have been published on long-COVID headache so far. Some case studies described the use of candesartan, amitriptyline, and onabotulinumtoxinA, which were noted as helpful for some, but not all, patients with long-COVID headache.

Also, some study results indicate that special considerations should be given to people who become infected and who previously presented with migraine. It has been noted that persistent changes in migraine characteristics can occur despite COVID-19 resolution.

The phenotype of headache and comorbidities should be taken into consideration while discussing the pharmacologic treatment for headache after COVID-19 infection. Lifestyle modifications and behavioral therapy should be discussed. Certain procedures that might be helpful include onabotulinumtoxinA injections and nerve blocks. In addition, a trial of neuromodulatory devices could be done. A multidisciplinary team approach is preferred, and advocacy should be in every patient treatment plan. With caregivers and patients working together, we will discover the best way forward.

REFERENCES
1. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. 

. 2018;38(1):1-211. doi:10.1177/0333102417738202
2. Martelletti P, Bentivegna E, Spuntarelli V, Luciani M. Long-COVID headache. Published online May 20, 2021. 

. doi:10.1007/s42399-021-00964-7
3. Bobker SM, Robbins MS. COVID-19 and headache: a primer for trainees. 

. 2020;60(8):1806-1811. doi:10.1111/head.13884 
4. García-Azorín D, Sierra Á, Trigo J, et al. Frequency and phenotype of headache in Covid-19: a study of 2194 patients. 

. 2021;11(1):14674. doi:10.1038/s41598-021-94220-6
5. Caronna E, Ballvé A, Llauradó A, et al. Headache: a striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution. 

. 2020;40(13):1410-1421. doi:10.1177/0333102420965157
6. Messlinger K, Neuhuber W, May A. Activation of the trigeminal system as a likely target of SARS-CoV-2 may contribute to anosmia in COVID-19. Published online August 18, 2021. 

. doi:10.1177/03331024211036665
7. Toptan T, Aktan Ç, Başari A, Bolay H. Case series of headache characteristics in COVID-19: headache can be an isolated symptom. 

. 2020;60(8):1788-1792. doi:10.1111/head.13940
8. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. 

. 2021;53(10):737-754. doi:10.1080/23744235.2021.1924397 
9. Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. 

. 2021;4(5):e2111417. doi:10.1001/jamanetworkopen.2021.11417

Articles

Although headache and COVID-19 have been linked together in the literature, more studies are needed to better understand the pathophysiology of these headaches and to determine the best treatment options.

The Therapeutic Space for People Living With Headache After COVID-19 Infection

“There is promise that if we would change the rate of administration in some cases, maybe from the beginning, we don’t have to observe any of the side effects because they’re not there.”

Dihydroergotamine (DHE) has been used in the treatment of migraine for quite a long period of time, and in recent years, the interest in attempting to optimize this oft used but somewhat unchanged therapy has increased.

One such attempt was conducted by Nina Riggins, MD, PhD, headache specialist, University of California San Francisco, and colleagues, the findings from which were accepted to be presented the 

American Academy of Neurology (AAN) 2020 Annual Meeting

. Their data, which assessed the impact of the infusion rate of intravenous DHE—in either 60 minutes or 90 to 120 minutes&mdash;on inpatient treatment outcomes, suggest that prolonging the infusion time to manage cramping led to an improvement of adverse effects without interfering with efficacy.

To find out more about the study and what the main takeaways are for the clinical community, 

reached out to Riggins for an interview. She provided her insight into the data, what research still needs to be done, and how intravenous DHE is being utilized now.

Riggins N, Ehrlich A, Corroo J, et al. Effect of Dihydroergotamine Infusion Rate on Inpatient Headache Treatment Outcomes. 

Videos

The headache specialist at UCSF discussed the findings of a retrospective assessment of the impact of the infusion rate of dihydroergotamine (DHE) on inpatient treatment outcomes.

Nina Riggins, MD, PhD: The Effect of Dihydroergotamine Infusion Rates

“Right now, in our center we administer 2 rounds of Botox and if patients report no significant improvement, in most of the cases 100 hours or more per month, we are moving onto different treatments. This study might be helpful for the people with moderate to severe cranial autonomic symptoms, if they get another ounce of Botox, they might improve too.”

At the 2019 American Academy of Neurology (AAN) Annual Meeting held in Philadelphia, Pennsylvania, Nina Riggins, MD, PhD, assistant professor and neurologist at the University of California San Francisco, and colleagues, presented findings from a chart review and survey of patients to determine whether the presence of cranial autonomic symptoms (CAS) predict headache benefit from Botox in adults with chronic migraine.

Among the 93 patients enrolled in the study, 9 subjects had no CAS at baseline, 34 subjects had mild symptoms at baseline, and 42 had moderate or severe symptoms at baseline. Investigators reported that 85 subjects had at least 2 rounds of Botox.

Of the subjects with mild CAS, 10 had a 50% or more reduction in headache frequency, of the 42 with moderate or severe CAS and 9 had a 50% or more reduction in headache frequency. Investigators reported that 37 of the 85 participants (39.78%) reported improvement in their CAS intensity.

This finding shows that patients without CAS were more likely to improve from treatment of Botox and those with moderate or severe CAS were less likely to respond to treatment. The investigators reported that Botox could improve CAS after multiple rounds, however, additional studies are needed to explore this finding.

spoke with Riggins in an interview at AAN.

Riggins N, Ehrlich A, Dapkus L, et al. Does the presence of Cranial Autonomic Symptoms in Chronic Migraine Patients Predict Efficacy of Botox Injections? Presented at: American Academy of Neurology 2019, Philadelphia, PA, May 4—10, 2019.

The assistant professor and neurologist at the University of California San Francisco discussed how the presence of cranial autonomic symptoms (CAS) can be a predictor of the effect of Botox on chronic migraine.

Nina Riggins, MD, PhD: Predicting Outcomes of Botox Treatment in Chronic Migraine

Dr Moawad is a neurologist and Clinical Assistant Professor at Case Western Reserve University and John Carroll University in Cleveland, OH, where she teaches undergraduate and medical students. 

She reports no conflicts of interest regarding the subject matter of this article. 

In this podcast, Dr Heidi Moawad interviews Nina Riggins, MD, PhD, a neurologist and researcher at the 

, San Francisco, CA. Dr Riggins discusses new, available treatments in headache medicine, including ongoing research about topical applications and other modes of treatment.

Heidi Moawad, MD (HM): You have done research about symptoms that predict necessity to repeat botulinum toxin injections. Can you describe any surprises? 

 Our study (currently in press) objectives were to determine whether the presence of 

 (CAS) can be a predictor of the effect of botulinum toxin injections on headache and whether the injections improve CAS in patients with chronic migraine.

In addition to a chart review, a survey was administered to current botulinum toxin patients at their visits to the UCSF Headache Center. Survey included questions on CAS such as redness of the white part of the eye, tearing from the eye, nasal congestion, runny nose, swelling around the eye, facial sweating, flushing, pupil looking smaller than usual, ear fullness.

Of the 93 patients enrolled in the study, 85 had at least 2 rounds of botulinum toxin and were included in the data analysis. Patients without CAS were more likely to improve from the treatment for chronic migraine, independently of medication overuse headache. Participants with moderate or severe CAS at baseline were less likely to respond to treatment

 could improve CAS and as symptoms improve, the efficacy of the drug could continue to improve after multiple rounds. Future studies need to explore whether patients with moderate to severe CAS would require more rounds of botulinum toxin in order to show improvement.

HM: When should neurologists anticipate hearing more about results of your study?

The study (with Peter Goadsby, PhD) is in press, and the poster, “Does the Presence of Cranial Autonomic Symptoms in Chronic Migraine Patients Predict Efficacy of Botox Injections?”, was submitted to the 2019 AAN Meeting in Philadelphia.

You are currently doing research about topical applications for migraine prevention. Which medications do you use and where do you place them?

Topical applications are done with anesthetic medications, such as lidocaine, bupivacaine, and ropivacaine. These medications are delivered by a Sphenocath®, an FDA-cleared device, to the region of 

 (SPG). The device does not have a needle and could be described as flexible catheter. A non-invasive procedure known as an SPG block places one of three different anesthetics under the study (lidocaine, bupivacaine, ropivacaine) into the nasal cavity and diffuses to the target in order to block the SPG nerve.

The SPG is located in the pterygopalatine fossa and has multiple connections to facial, trigeminal, parasympathetic, and sympathetic systems which make it a promising target for migraine treatment. SPG blocks are quite commonly performed at the headache center at UCSF to treat chronic migraine, and patients have reported significant relief.

 Scientific Meeting in 2018 titled “Preventive Effects of SPG Blocks in Chronic Migraine Patients Increases With Number of Repeated Blocks.” It was a chart review study that concluded that the SPG block is a safe and effective preventive treatment in chronic migraine. It helped to reduce use of acute (as needed) headache medications in 18 out of 20 patients who received 4 or more SPG blocks with lidocaine.

We would like to determine if the frequency and medications that we use as our standard of care in the clinic prove to be significantly better than placebo and also to see if there is a difference in the anesthetics we use. We submitted the study to the IRB (Institutional Review Board) and received approval for the SPG block randomized placebo-controlled trial.

1. To determine whether SPG blocks can be effective in migraine headache prevention at a lower frequency of administration than in previous studies.

2. To determine if there is a difference in efficacy between lidocaine, bupivacaine, and ropivacaine.

3. To determine whether the repeated use of SPG blocks every 2 to 4 months for 3 treatments will have a cumulative effect, with subsequent treatments providing better and longer lasting effects on headache frequency and severity.

4. To determine if repetitive SPG blocks can reduce the need and use of acute treatments and emergency room visits

Is there a certain patient subtype that is more likely to respond to treatment?

 There is a possibility that patients with 

 could greatly benefit from this procedure. We noted that the SPG block was the treatment that broke the daily cycle of pain for the patients in this group. Whether it is statistically significant needs to be determined by the future studies.

You mentioned a bad taste as an adverse effect of the procedure. How long does it last? 

Bad taste usually resolves within a few minutes, up to an hour after procedure.

Do neurologists need special training to learn how to use the topical treatment? 

There are various methods for performing SPG blocks, some of which are more invasive and risk-prone than using catheter applications. The new catheter application option, which we started to utilize a couple of years ago, is easy to use and we are teaching our headache fellows and other colleagues in neurology how to use it with success.

Editor's note: This article was posted on February 6, 2019 and has since been updated.

In this podcast, Dr Heidi Moawad interviews a neurologist currently researching new, available treatments in headache medicine.

Nina Riggins, MD, PhD

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The Therapeutic Space for People Living With Headache After COVID-19 Infection

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Nina Riggins, MD, PhD: Predicting Outcomes of Botox Treatment in Chronic Migraine

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