Skip to main content

Author Question & Answer Blogs

Q&A with Javier Trigo and David García-Azorín

New Content ItemJavier Trigo is a general neurologist and clinical research. Is is currently researching on COVID-19 headache.



New Content ItemDavid García-Azorín is a neurologist and clinical researcher
focused on headache disorders. His main areas of interest are headache in the emergency room, other headache disorders and recently, headache in COVID-19


Please briefly introduce yourself, your co-authors, your respective fields of expertise, and the context/premise of your article.

We are a group of researchers focused on clinical research. Most of us are neurologists, which collaborate with the engineer team of the Imaging Processing Laboratory. Most of our contributions were related with the clinical characterization of migraine, other primary headache disorders, as nummular headache and some secondary headaches, including alcohol-induced headache, and headache in cerebral venous sinus thrombosis. We have also contributed to the description of some cranial neuralgias, with some publications about occipital neuralgia and terminal branch neuralgias. The COVID-19 pandemic interrupted all our clinical and research activities, but it also offered an excellent opportunity to study about the COVID-19 related headache.

Could you please give a short summary of your article and its findings/conclusions?

Headache is one of the commonest symptoms of COVID-19. In our series, approximately a fourth of patients described it. In the present study (Trigo, J., García-Azorín, D., Planchuelo-Gómez, Á. et al. Factors associated with the presence of headache in hospitalized COVID-19 patients and impact on prognosis: a retrospective cohort study. J Headache Pain 21, 94 (2020). https://0-doi-org.brum.beds.ac.uk/10.1186/s10194-020-01165-8), the research question was why some patients present headache during the course of the COVID-19 disease while other patients deny it. We compared a significant number of demographic variables, clinical symptoms and laboratory parameters. After adjusting for the different confounders and effect modifiers, we observed that some symptoms were more frequently described by patients with headache, including anosmia, myalgia and fever. In addition, the inflammatory response seemed less severe, since they had lower levels of C-reactive protein, D-dimer, Lactate Dehydrogenase, ferritin or interleukin-6; while lymphocyte count was also higher.

Indeed, we observed that patients with headache had a lower all-cause in-hospital mortality, when compared with patients without headache. Given that patients with headache were younger, more frequently female and with a better baseline situation, we had into account all those variables into the mortality risk analysis, and headache was still a factor associated with a better prognosis.

What are the implications of your article’s findings or the conclusions that could be drawn for practice, research, policy, or public health?

Headache is one of the most disabling symptoms of COVID-19. The findings of our study may suggest that it could be related with a more efficient immune response. Further researchers have analyzed the inflammatory response in patients with headache, compared with those without headache. One of the lessons from our study is that those calculations should always be adjusted for all the relevant covariates, including age, sex of patients, presence of comorbidities. The reason is that patients with headache seem to have a different demographic profile, and even when a study do not find statistically significant differences when comparing patients with and without headache, this may be related with a lack of power of the study, if the sample size is modest.

The study of different novel and repurposed drugs for the treatment of COVID-19 has not yielded the expected results. The better understanding of the pathophysiology of headache could give important insights, since in patients with headache, the innate and acquired immune response is capable to effectively defeat the virus.

Where do you think the knowledge gaps still lie, and what challenges does this research face in the future?

We think that there is still an important gap in terms of how SARS-CoV2 produces neurologic manifestations and, more specifically, how it causes headache.  It has been hypothesized with a direct invasion of the virus into the central nervous system or hypoxia as cause of the headache, however it seems that in most patients, the most plausible hypothesis is that headache in COVID-19 may share criteria and mechanisms with headache related to systemic viral infections.

Next steps should analyze the changes in neuroimaging in patients with acute and persistent headache after COVID-19, and which treatments are most effective in the treatment of this disabling symptom. The frequency and causes of the persistence of headache after the acute phase of the disease are still uncertain.

Finally, are there any new developments in research surrounding chronic headache or pain etiology that you think are particularly exciting?

The phenotypic characterization of secondary headache disorders may help us to better understand the pathophysiology of primary headaches. Personal and familiar biology may influence on the risk of having certain phenotypes, as migraine-like phenotype; however, the influence of environmental factors may be also critical. The more we understand the causes, the closer will get from the cure and effective treatments.

Q&A with Álvaro Planchuelo-Gómez, David García-Azorín, Javier Trigo

New Content ItemÁlvaro Planchuelo-Gómez is currently a PhD student in Telecommunications Engineering at the University of Valladolid, Spain. His research is focused on multimodal brain MRI processing using T1-, diffusion-weighted, and functional MRI and their statistical analysis.


New Content ItemDavid García-Azorín is a neurologist and clinical researcher focused on headache disorders. His main areas of interest are headache in the emergency room, other headache disorders and recently, headache in COVID-19.

Please briefly introduce yourself, your co-authors, your respective fields of expertise, and the context/premise of your article.

Álvaro Planchuelo-Gómez, Santiago Aja-Fernández and Rodrigo de Luis-García are engineers of the Imaging Processing Laboratory (Valladolid, Spain). David García-Azorín and Ángel Luis Guerrero are neurologist of the Headache Unit of the University Hospital of Valladolid (Spain). Margarita Rodríguez is radiologist of the Department of Radiology of the University Hospital of Valladolid (Spain). We are a team mainly composed of telecommunications and biomedical engineers specialized in Magnetic Resonance Imaging (MRI) processing and neurologists specialized in Headache disorders. With regard to the context of our article, there was barely research about diffusion MRI comparing patients with chronic migraine (CM) and episodic migraine (EM), and the sample size of previous studies was low.

Could you please give a short summary of your article and its findings/conclusions?

In this study (Planchuelo-Gómez, Á., García-Azorín, D., Guerrero, Á.L. et al. White matter changes in chronic and episodic migraine: a diffusion tensor imaging study. J Headache Pain 21, 1 (2020). https://0-doi-org.brum.beds.ac.uk/10.1186/s10194-019-1071-3), we aimed to compare the white matter integrity in patients with migraine, with respect to controls. We studied not only chronic migraine patients but also episodic migraine, which were not always included in similar studies. We processed diffusion MRI data from patients with CM, EM and healthy controls to obtain scalar measures based on diffusion tensor imaging (DTI) to define white matter integrity in the center of diverse tracts. Furthermore, we assessed the correlation between clinical parameters and the DTI descriptors. The most important findings of our study are the identified differences in most white matter regions between CM and EM and the correlation between the time from onset of CM and DTI-based measures, reflecting a possible maladaptation in stable CM.

What are the implications of your article’s findings or the conclusions that could be drawn for practice, research, policy, or public health?

The findings of our article suggest that CM and EM are associated but distinct entities that follow different temporal pathways with respect to white matter changes. Particular characteristics of CM should be considered in comparison with low-frequency EM (the EM patients included in our study). Future studies should try to find neuroimaging EM and CM specific biomarkers that may help to better understand the diverse pathophysiological mechanisms taking place in both types of migraine, and to evaluate whether the changes that were observed in patients with CM revert when patients improve and turn back to a lower frequency of headache episodes.

Where do you think the knowledge gaps still lie, and what challenges does this research face in the future?

Regarding structural alterations observed in the brain of patients with migraine, it is unknown whether these changes are cause or consequence of migraine. Longitudinal studies including healthy young subjects with family history of migraine would contribute to elucidate this question. Other longitudinal studies focusing on CM may help to understand migraine chronification or differences between patients with a positive and no response to the treatment. With respect to diffusion MRI and migraine patients, most studies have employed the DTI model and low sample size, which limits the potential to find differences between the migraine groups and controls. Future studies should consider the use of alternative diffusion models with higher sample size, taking into account different groups of patients with CM and EM. In our study, we prioritized the study of patients with low-frequency episodic migraine, since there may be some overlap between high-frequency episodic migraine and CM. Moreover, little is known about the specificity of the structural differences in the brain of patients with headache disorders, which have been also described in other painful syndromes (e.g., fibromyalgia). Some changes could be related with the presence of pain, whereas others could be more migraine-specific.

Finally, are there any new developments in research surrounding chronic headache or pain etiology that you think are particularly exciting?

The new anti-CGRP (calcitonin gene-related peptide) migraine treatments and their effects on brain function and structure are a very thrilling field to better understand the migraine pathophysiology. In addition, the extraction of specific EM and CM neuroimaging biomarkers may be useful to predict treatment response and prescribe personalized treatments. Another exciting research field is the relationship between structural and functional alterations in migraine, considering gray matter and white matter changes in sophisticated multimodal approaches with special focus on structural and functional connectivity.

Q&A with Dr Jasem Al-Hashel and Dr Ismail Ibrahim Ismail

New Content Item  New Content Item

Please briefly introduce yourself, your co-authors, your respective fields of expertise, and the context/premise of your article.

Dr Ismail Ibrahim Ismail is a neurology specialist who graduated from Alexandria University, Egypt in 2006, and received a master’s degree in neuropsychiatry from the same university in 2013. He became a Fellow of the European Board of Neurology (FEBN) in 2017, and he received MRCP Specialty Certificate in Neurology in 2019. He is currently running neurology clinic in Ibn Sina hospital, Kuwait since 2013. Dr Ismail has been involved in a number of research trials, and he has several international publications, book chapters, and presented research in several international conferences.

Dr Jasem Y. Al-Hashel is an adult neurology and headache consultant. He completed his neurology residency as well as his fellowship in headache and Botulinum toxin injection at McGill University, Canada. He is board certified from the Royal college of Physicians and Surgeon of Canada (FRCPC), American fellowship in Headache Medicine (FAHS) and Canadian fellowship in Headache Medicine from McGill University. He is currently an associate professor of neurology at Kuwait University, the Chair of the Faculty of Neurology in Kuwait and the President of Kuwait Neurological Society and the Vice President of Pan Arab Union of Neuroscience (PAUNS)

Could you please give a short summary of your article and its findings/conclusions? 

In our study ( Al-Hashel, J.Y., Ismail, I.I. Impact of coronavirus disease 2019 (COVID-19) pandemic on patients with migraine: a web-based survey study. J Headache Pain 21, 115 (2020). https://0-doi-org.brum.beds.ac.uk/10.1186/s10194-020-01183-6) we aimed at investigating the “real-world” impact of COVID-19 pandemic on patients suffering from migraine, and on the quality of care they received during this unprecedented healthcare crisis.  We also aimed at identifying risk factors for poor outcomes in those patients.

We conducted a web-based survey study that assessed multiple domains including demographic variables, frequency and severity of migraine attacks, patient’s ability to get proper medical care, symptoms of depression, anxiety, insomnia, perceived stress, analgesics overuse, the use of other traditional/alternative remedies, and other patient’s COVID-19-specific concerns during the pandemic.

A total of 1018 patients with migraine were recruited from our headache clinic registry at Ibn Sina hospital, Kuwait, and via several social media outlets. We found that COVID-19 pandemic had an overall negative impact on those patients, as more than half of the respondents experienced increase in migraine frequency and worsening of headache severity, in comparison to the pre-pandemic period, and around 10% transformed to chronic migraine. This was understandably accompanied by overuse of analgesics and acute migraine treatments, use of traditional/ alternative remedies, however, few patients visited ED, probably for fear of contracting the virus.

We also found that female gender, shorter disease duration, having difficulty in getting medications, lack of communication with treating neurologist, non-compliance to treatment, and working during the pandemic, had a statistically significant correlation with worsening of migraine symptoms. Moreover, symptoms of anxiety and/or depression, disturbance of sleep and eating habits, lack of regular exercise, overuse of analgesics and use of traditional medicine, were significantly higher in this group. 

What are the implications of your article’s findings or the conclusions that could be drawn for practice, research, policy, or public health? 

The ongoing threat of COVID-19, or other future pandemics, will require long-term strategies to deliver quality care for patients with migraine. Telemedicine has become an essential modality for headache specialists. We believe that communication with the treating neurologist, regardless the method itself, is of utmost importance to good outcome. We should prepare our patients with “rescue care” plans and self-administered therapies, to keep patients away from ED and limiting their exposure to COVID-19. Also, home delivery of medications was done successfully in Kuwait during the lockdown period.  Patients with migraine should be educated and advised to stick to their previous routine as much as possible. Maintaining regular sleep hygiene, healthy diet, and good hydration are important, in addition to avoiding information overload, self-isolation and excess screen time exposure.

Where do you think the knowledge gaps still lie, and what challenges does this research face in the future?

In our study, we attempted investigate the impact of the pandemic on patients with migraine, that has not been studied before, to our knowledge. However, we understand the limitations of observational survey studies, and that establishing a direct causal relationship can be difficult. However, we presented the first “real-world” evidence of the negative impact of an unprecedented global crisis on patients with migraine, with an overall adequate sample size. We believe that further large population-based studies are still needed to confirm our findings. We hope our study can be used to help planning and implementing future long-term strategies.

Finally, are there any new developments in research surrounding chronic headache or pain etiology that you think are particularly exciting?

I believe that treatment of chronic migraine is a dynamic and rapidly advancing area of research. The recent approval of several anti-CGRP/R monoclonal antibodies and CGRP receptor antagonists had offered a new hope for those patients, and opened the door for a more personalized approach in treating patients. I also think that the need for biological and clinical markers of therapeutic efficacy is needed now more than ever, to establish the proper targets, thus maximizing the cost-effective use of these treatments. Moreover, despite the current evidence on available neurostimulation-based and neuromodulatory treatment techniques, I still think that further studies are needed to confirm their efficacy in chronic migraine.

Q&A: Pamela Blake, MD

Pamela Blake MD
University of Texas Health Science Center at Houston

Houston, TX,  SA

Please briefly introduce yourself, your co-authors, your respective fields of expertise, and the context/premise of your article

I am a neurologist.  I originally trained in Neuro-Ophthalmology in 1995, yet was increasingly drawn to Headache Medicine.  I found the behavioral aspects of headache fascinating, and the options for treatment were much wider in Headache Medicine than in Neuro-Ophthalmology.   After several years on the faculty at Georgetown, I relocated from Washington DC to Houston in 2006, and the hospital system which employed me there offered to me the opportunity to open a practice solely devoted to Headache, so at that point my practice became 100% Headache Medicine.   I opened a private practice in 2019.

In 2004 I became exposed to nerve decompression surgery for chronic headache.  Why the surgery should work was unclear at the time, as the prevailing opinion seemed to be that the pain of chronic headache emanated from central, or at least intracranial, processes. The surgery was very helpful for many of the patients, however, and became an important part of my practice by 2006.   In 2009 I met Rami Burstein, and our collaboration began.  Rami needs no introduction to the readers of this journal, as he is a highly regarded and widely published researcher from Harvard University.  Rami observed several surgeries with my surgical colleague, Dr. Carlton Perry.  Rami observed in the OR the compressive inflammatory tissue surrounding the occipital nerves.  He rightly recognized the important role of this tissue in the mechanism of nerve compression, and he directed our research efforts accordingly.  Our work over the years with regard to both basic science and clinical treatments has contributed to a growing understanding of the anatomy and pathophysiology of nerve compression and its role in chronic headache, as explained in the article, as well as how nerve compression headache may coexist with other, more clearly centrally-driven processes such as episodic migraine with aura.

Could you please give a short summary of your article and its findings/conclusions? 

Our article ( Blake, P., Burstein, R. Emerging evidence of occipital nerve compression in unremitting head and neck pain. J Headache Pain 20, 76 (2019). https://0-doi-org.brum.beds.ac.uk/10.1186/s10194-019-1023-y) is a brief overview of current knowledge regarding the causes of pain in migraine, as well as a review of the pathophysiology of superficial nerve compression in chronic headache that is characterized by unremitting head and neck pain (UHNP), usually with associated occipital allodynia and cervical muscle spasm.  The etiology of the pain of chronic headaches is not known.  We do know is that many centrally directed treatments appear not to be effective, as they are often abandoned.  Additionally, over the last 10-20 years, the role of treatments directed primarily at the periphery, such as botulinum toxin and CGRP monoclonal antibodies, has grown exponentially.  These findings may be suggestive of a peripheral and even extracranial factor in chronic headaches, and superficial nerve compression is a candidate factor as the etiology of chronic headache.  

The article goes on to review the mechanism of anatomic compression of the occipital nerves within the cervical musculature and the reasons for which inflammatory tissues may develop around the nerves, leading to further nerve compression and gradually increasing pain.  This raises fascinating questions… for example, might this be a contributing factor to the so-called transformation from episodic migraine to chronic migraine?   We touch briefly on the role of nerve decompression surgery, which continues to be an important part of my clinical practice

What are the implications of your article’s findings or the conclusions that could be drawn for practice, research, policy, or public health? 

Ten years after the approval of Botox in the United States and the EU as an effective treatment of chronic migraine, chronic headache continues to be a leading cause of disability in both of these countries.  Clearly, we have much more to learn and to offer regarding the etiology of chronic head and neck pain.  I hope that pursuing research of peripheral factors including nerve compression, and, leading from that, the effect of nerve decompression in treating pain, will be a significant focus in Headache Medicine going forward.  

Research in this area has been hampered by several factors: (1) the paradigm shift that is involved in considering extracranial and cervical factors as a possible main cause of chronic headache in some individuals; (2) challenges in conducting research on nerve decompression surgery, ranging from the lack of a clear funding source to the ethical challenges of conducting controlled clinical trial that would require sham (four- hour long, in the prone position) surgery, and (3) the lack of wider collaboration between Headache Medicine practitioners and plastic surgeons.  This last factor has been particularly problematic.  It has resulted in plastic surgeons identifying patients who they deem to be good surgical candidates and operating independently, and mistakes have been made in this regard.  I think however that this moment should be an inflection point for the treatment of chronic migraine.   I believe that the practice model that my current practice embodies, with the close collaboration of  Headache Medicine, Plastic Surgery, Psychology (for both formal testing and treatment), and Physical Therapy is necessary, and should be the model for what Headache Medicine should look like in the future.

Where do you think the knowledge gaps still lie, and what challenges does this research face in the future?    

We now know that pathophysiology in the occipital nerves that can lead to chronic headache with migraine features.  Critical to this knowledge is the unravelling of the culprit.  What causes the occipital nerves to be irritated?  Is it anatomical malformation?  Is it cellular, molecular or genetic deviation from normal?  Is it inflammatory?  Is it neuropathic?  Is it secondary to muscular pathology?  Does it originate in sick nerves or the tendons or bones they innervate?      We know from cadaver studies that the anatomic placement of the occipital nerves within a cervical muscle is high – anywhere from 40-80% of cadavers – yet surely, and fortunately, 40-80% of people are not experiencing unremitting head and neck pain.    It follows that the differentiating factor might be inflammation.  What is the cause of the inflammation?  The factor that I find most interesting and challenging and which flummoxes me on an almost daily basis is the role that stress and emotional factors play in pain.  Certainly, we know from numerous excellent studies that stress is a very common trigger for episodic migraine.  But what is its larger role in the development of chronic pain?  Many of the patients I see with UHNP report the onset of their pain during a period of intense stress; the stress eventually abates, yet the pain persists.  What role does that stress have in that situation?   And what about those individuals with early life adversity?  Often these are our most challenging patients.  It has been shown that stress may affect inflammatory processes.  Might chronic inflammatory effects be a cause for UHNP in these individuals?  Of note, management of common comorbidities, particularly psychological conditions, is a critical aspect of successful reduction in headache during the process of nerve decompression.

Regarding challenges to research, many exist.  Regarding surgery, the lack of a true placebo group is a major challenge.  It is not possible, for ethical and safety reasons, to have a placebo group for a long surgery under general anesthesia in the prone position.  The lack of a funding source is a second obstacle.  A third is the need for the dissemination of more consistent surgical methods.  Some individuals may have as many as eight branches of the lesser or greater occipital nerve, each of which is compressed within cervical musculature.  The necessary surgical procedure requires systematically identifying and decompressing all the nerve branches, while leaving all the nerves intact.   This results in a four-five-hour long procedure.   There is currently wide variation among surgeons as to how the surgery is conducted, and Dr. Perry and I have seen the results of surgery performed by individuals who have not had proper training.   Incorrectly performed surgery is not only harmful for the patient, it is harmful to the broader perception of the treatment.   Finally, new metrics for research design are needed to separate out the effects of surgery on the pain caused by nerve compression from, for example, lingering migraine headaches triggered by stress or hormonal fluctuations.

Finally, are there any new developments in research surrounding chronic headache or pain etiology that you think are particularly exciting? 

The current focus in Headache Medicine is on the role of CGRP and the effects of blocking its actions with antibodies that work largely in the periphery.  This is indeed a fascinating area that dovetails with the concept of extracranial nerve compression.  I am also excited by the growth of the field of psychoneuroimmunology, devoted to science of the interactions of mind and body, and what it can teach us about behavioral interventions such as mindfulness and meditation, and their effects on hormonal and inflammatory processes.

Q&A: Favoni Valentina, MD

Dr Valentina Bio

Favoni Valentina, MD

Neurologist, IRCCS of Neurological Sciences of Bologna in Italy

Could you please give a short summary of your article and its findings/conclusions?

Calcitonin gene-related peptide (CGRP) is a small molecule shown to be released during migraine attacks. In the last two years, the use of monoclonal antibodies targeting CGRP has become a concrete, valuable addition as a preventive treatment for migraine patients. Considering the action of CGRP as a highly potent vasodilator, some reasonable concerns on the impact on cardiovascular health have been raised. The article reviewed the evidence on the role of CGRP in the cardiovascular system in order to understand the possible cardiovascular effect of CGRP blockade with monoclonal antibodies in migraineurs. Despite the aforementioned cardiovascular implication, treatment with CGRP antibodies has shown no relevant cardiovascular side effects.

What are the implications of your article’s findings or the conclusions that could be drawn for practice, research, policy, or public health?

Migraine is a very disabling disorder with severe impact on patients' lives for many years and substantive costs to society in terms of healthcare costs and lost productivity. For each patient, we have to decide whether the benefits of treatment outweigh the possible risks. The cardiovascular safety of a preventive treatment is a key element to consider. With this in mind, CGRP monoclonal antibodies ore a valid option for migraine treatment.

Where do you think the knowledge gaps still lie, and what challenges does this research face in the future?

Certainly, these CGRP monoclonal antibodies class of drugs have been safe compounds for the short-term. There are significant long-term adverse effects that need to be considered after these new products entered the market. The safety profile of CGRP monoclonal antibodies in high-risk patients has to be specifically addressed in real life. We will have a better feel for the true risk in 10 years.

Finally, are there any new developments concerning the effects of CGRP on the cardiovascular system, or CGRP and migraines in general that you think are particularly exciting or compelling?

Published articles regarding CGRP monoclonal antibodies during 1‐year-treatment studies and reports on longer exposures (up to three-years) suggest ongoing safety such that cardiovascular events and adverse invents in general continue to remain infrequent.