Migraine in Famous People: The Case of Christiaan Huygens

By Peter J. Koehler

Christiaan Huygens; painting by Caspar Netscher (public domain).

Christiaan Huygens; painting by Caspar Netscher (public domain).

Many famous persons, today as well as in the past, suffer(ed) from migraine. With a prevalence of around 16% for women and 8% for men, it ranks high in the Global Burden of Disability.1 Going back in history, it may be difficult to make a retrospective diagnosis, in particular, if not all symptoms, as described in current diagnostic classifications, are mentioned. However, the disability can often be recognized quite easily, as in the following case. In this essay, I will discuss a 17th century scientist, who was suffering from frequent headaches, possibly migraine.

Conversation in Latin at Age 9

Christiaan Huygens (1629-1695) was born in The Hague (Netherlands) as the second son of Suzanna van Baerle (1599-1637) and Constantijn Huygens (1596-1687), who had been a diplomat and secretary of two Princes of Orange. Constantijn was also a poet and composer. He was interested in the arts and is considered by some the discoverer of the talent of Rembrandt (and Lievens), who at the time were working in nearby Leyden. He was acquainted with Descartes and played an important role in the publication of his Discours de la méthode (Dioptics). Most probably, they first met at Hofwijck castle, Huygens’ summer residency just outside of The Hague, in May 1642. Descartes wrote about Constantijn Huygens. “The honour to know him I cherish as one of the most happy things that happened to me.” Huygens wrote about Descartes: “Truly, he is a man superior to all esteem that one would wish to render him.”

Design for a microscope in letter to his brother Constantijn 1678.9

Design for a microscope in letter to his brother Constantijn 1678.9

Christiaan was educated at home and excelled in nearly all subjects. He was able, for instance, to converse in Latin at age 9. Following a two-year study period of law and mathematics at Leyden University, he continued his studies at the Orange College in Breda. Despite his father’s wish to become a diplomat, Christiaan was interested in mathematics rather than law. He, as well as his father, corresponded with the French philosopher and mathematician Marin Mersenne (1588-1648). Constantijn called his son “mon Archimède,” in imitation of the Mersenne, who had noticed the remarkable gift of young Christiaan and encouraged him to continue his mathematical studies.

Designs for an Improved Microscope

Brass microscope with five diaphragms and object revolver for six specimens after design by Christiaan Huygens (c 1680). Courtesy Boerhaave Museum, Leiden (V 26952).

Brass microscope with five diaphragms and object revolver for six specimens after design by Christiaan Huygens (c 1680). Courtesy Boerhaave Museum, Leiden (V 26952).

Thus, Christiaan became famous as mathematician, physicist (considered a founder of mathematic physics), and astronomer, who corresponded with and became Fellow (1663) of the Royal Society (London), as well as member (and research director) de l’Académie des Sciences (Paris). At the latter academy, he was served and paid by King Louis XIV. Christiaan invented the pendulum clock2 and described light as a wave phenomenon;3 moreover, he discovered the moon Titan of Saturnus (1655; publication of De Saturni Luna observatio nova in 1656). He constructed a variety of optical instruments, often in close association with his older brother Constantijn.4 He not only used telescopes, but was also interested in microscopes. Already in the 1650s, the brothers had compound microscopes. Christiaan’s enthusiasm for this instrument increased after he had translated and presented the work of Antoni van Leeuwenhoek at the Paris Académie. He also wrote to Nehemia Grew (1641-1712), the Secretary of the Royal Society in London, that he “directed [his] mind to constructing a new microscope, excited by that new observation, which shows that the semen is full of living vivacious animalcula.”5 As Van Leeuwenhoek’s letter was published in the Philosophical Transactions only a year after receipt, Huygens’ short description became the first.4 Not satisfied with Leeuwenhoek’s original instrument, Huygens made six designs of an improved simple microscope with a diaphragm revolver as well as a specimen revolver. The improvement concerned the quality of the image and the manipulation of the specimens.4 In August 1678, he wrote to his brother about a more practical type of microscope. The design was used by several instrument makers.

Incapacitating Headache

In the 22-volume Oeuvres Complètes (OC 1888-1950), that includes his correspondence (in Latin, German, English, and Italian) and writings, mainly written in (old) French, interesting information can be found about his chronic headache.

In 1652, in a letter to Frans van Schooten junior, who was professor of mathematics at the University of Leyden, Christiaan wrote about his headaches for the first time. He must have been 23 years old. Due to headache that was not always present, but occurred at the most inconvenient moments, he was often unable to work, unless he was able to overcome the pain by willpower. About 10 years later, we learn about the treatment that was applied as advised by his physician. In a letter to his younger brother Lodewijk, he complained about his headaches and mentioned that he had had himself bled and purged. These kinds of treatments were indeed quite common and should be explained in the context of contemporary humoral medicine.7

Since my latest [letter] I have taken advise of our medic Libergen [sic], who had me purged and bled, having done that, I had a nasty cold as I have never known to have had, in such a way that I not only have to stay at home, but also have to abstain from reading, writing, or meditating, because as soon as I do I have a headache.

The Liebergen family counted numerous physicians. Huygens probably referred to Willem van Liebergen (1601-1674), who had studied philosophy and medicine at Leyden University.

Christiaan had to apologize himself regularly for his behavior due to headache. After he moved to Paris and became a member of the new Académie Royale des Sciences, he wrote to the husband of his sister Susanna that due to headache, he had been unable to write him, although he usually was punctual with this respect. He still felt some remnants of the latest period.

A few months later, in November 1666, he wrote to the same person that writing caused headache. In 1677, Constantijn sr. wrote about his son’s health. “My Archimedes has recovered well enough from his ailment, although always frail and subject to headaches.” A year later, Constantijn jr. wrote, “My brother has a severe headache.” At age 56, Christiaan was still suffering from headaches, writing “I have written a part of the memoirs, as you know and would have completed it without headaches that, since Easter day, have annoyed me and by which, still today, I did not go outside.”

Half a year later, he wrote again to his brother Constantijn that “since three days there is a constant fog here that gives me very annoying migraines.” In the spring of 1686, he wrote to the same brother that next to an inguinal hernia, he was still suffering from headaches. “Meanwhile I am suffering as you may believe, in addition I have been tormented anyhow all these days by my migraines, that now begin to leave me.”

Correspondence With European Scientists

In his correspondence with many famous persons of the period, Christiaan sometimes referred to his headache. In January 1664, the French poet and critic Jean Chapelain (1595-1674), who also corresponded with Constantijn sr., wrote to Christiaan: “I am glad at least about the relief that you experienced with respect to you headache.” Toward the end of that year, Christiaan wrote to natural philosopher Sir Robert Moray (1608-1673), one of the founding members of the Royal Society, “Not having been able to respond in the usual way, I should not let leave the mail another time without acquitting myself of this duty despite an annoying headache that lasted this whole day and brings me in a mood of rather doing nothing.” Moray responded:

All your letters oblige me very much. However, your latest of the 21st does so even more than all previous ones. Writing me a long letter, full of nice things, while a headache tempts you not to do anything, well deserves to be estimated as a very special sign of extraordinary affection, it is therefore quite reasonable that I write a prompt and, as much as I can, satisfactory response.

And in 1692, in a letter to the German philosopher and mathematician Gottfried W. Leibniz (1646-1716), with whom he wrote on the mathematization of physics and on whom he had an important influence, he wrote: “I am very obliged for showing interest in my health, that since my last [letter] has suffered much from migraine during that long freeze.”

Mother and Sister Suffering Too

A hereditary factor may have played a role in Christiaan’s headache as his sister Susanna (1637-1725) wrote about her own migraine in 1680. “It is to my great regret, my dear brother, that I learn … that you have been uncomfortable by pain and heat in the head … I hope to learn soon that you will not complain anymore. I certainly have my part of migraine sometimes, and I complain more than anybody of those, who suffer of similar discomforts.” Christiaan and his sister may have inherited the affliction from their mother. She suffered from migraine and menstruation troubles, for which she had to be put a diet and was prescribed bleeding as well as purging.

Treatment With Water and Tea

In August 1654, Christiaan stayed in a spa in the mountains of the eastern part of the present Belgium. This was a well-known town with healing cold mineral springs since the 14th century that had resulted in the eponym spa. His father was staying there too and took water a couple of times. In one of the poems written for Mdm Emilia de Mérode-van Wassenaar during a stay, Constantijn Sr. wrote about migraine (1654):

Trouvez vous pas quelque migraine
Qui vous eschauffe le cerveau?
Si ma conjecture n’est vaine
Il vous reste tant soit peu d’eau

[Don’t you feel any migraine
That sets on fire your head?
If my diagnosis is right
Water is the only cure to save you]

Constantijn Sr. probably used the water more often than his son Christiaan, who was rather critical about its healing effects.

In the first half of the 17th century, tea was used as a remedy and reserved to high society. In the course of the century, however, it became more widespread and not just as a drug. Next to purging and bleeding, Christiaan indeed drank tea and apparently was satisfied about it. In 1663, still staying in Paris, he wrote to his brother Constantijn “If there is a way to send me … a pound or a half of the good tea, you would do me a great pleasure, as, since some weeks, I have felt myself admirably well by only taking the leafs in the mouth, as soon as I feel myself indisposed by headache, because that cures me without fail.” Furthermore, water cures, as usual at the time,7 were attempted.

Migraine and the Use of Optical Instruments

Letter by Huygens to Leibniz (1692) (from Oeuvres Complètes vol. 10, p. 268).

Letter by Huygens to Leibniz (1692) (from Oeuvres Complètes vol. 10, p. 268).

During the 19th century, migraine, in particular migraine with aura, was associated with scientists, who were using optical instruments. French physicist and astronomer Dominique François Jean Arago (1786-1853), Scottish physicist David Brewster (1781-1868), and British Astronomer Royal George Biddell Airy (1801-1892) are persons often referred to. Airy’s son, the physician Hubert Airy (1838-1903), who was also a victim to visual auras, believed it had its origin from their habits of accurate observation leading to intensive eye-work and brain-work, exposing them to the risk of impairment of the eyesight. He gave some striking descriptions of his own auras and added several figures of his experiences. The aura was emphasized rather than the headache. There is no indication that Huygens was suffering from auras.

Comorbid Depression

The recurrent episodes, some of which being clearly incapacitating, and familial occurrence suggest that Huygens was suffering from migraine, although some symptoms that would be expected were not described. Another aspect of his health was that he went through at least two periods of melancholia hypochondrica, notably in 1670 and 1676. Assuming we would diagnose this disease as a depressive disorder today, we know this is associated with migraine. And of course, melancholy was considered the disease of scholars at least in the century that started a few years after Christiaan Huygens’ decease in 1695. •

 

References

  1. Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z; Lifting The Burden: the Global Campaign against Headache. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020;21:137
  2. Huygens C. Horologium Oscillatorium sive de motu pendulorum. Paris, Muguet, 1673.
  3. Huygens C. Traité de la lumière, Leiden, Pieter v.d. Aa, 1690.
  4. Fournier M. Huygens’ designs for a simple microscope. Annals of Science 1989;46: 575-596.
  5. Huygens C. Oeuvres Complètes X. Correspondence of June 6, 1678. No. 2125 ; p. 77 (translation in ref. 3).
  6. Koehler PJ. Huygens’ headache. Cephalalgia. 2015;35:1215-9.
  7. Koehler PJ, Boes CJ. A history of non-drug treatment in headache, particularly migraine. Brain. 2010;133:2489-500.
  8. Koehler PJ, Boes CJ. History of Migraine. In: Swanson et al. eds. Migraine. Handbook of Clinical Neurology. In press.
  9. Huygens C. Oeuvres Complètes VIII. Correspondence of August 11, 1678. No. 2133 ; pp. 90-3.

Candidate Statement for Elected WFN Trustee

Alla GuekhtAlla Guekht

It has been a tremendous privilege to serve as Elected Trustee of the World Federation of Neurology with the rich tapestry of more than 120 national societies and hard work of the most talented professionals in neurology in the world. It was a great honor to be able, especially at the challenging times of COVID-19 pandemic, to contribute to achieving the WFN mission to foster quality neurology and brain health.

As the trustee of the WFN, I have become integrated into its outstanding multifaceted work. I have learned so much from our president, esteemed colleagues in the Board of Trustees, WFN committees, regional and national organizations, neurologists from many countries of the world, and the WFN staff members.

In my role as the WFN trustee, I contributed to the successful development of the collaboration with the WHO. Adoption of the Resolution WHA 73_R10: Global Actions on Epilepsy and Other Neurological Disorders was the landmark event and unprecedented recognition of the global importance of these conditions; the WHO made a commitment to develop a 10-year Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and to include in this plan “ambitious, but achievable, global targets on reducing preventable cases of, and avoidable deaths …, strengthening service coverage and access to essential medicines, improving surveillance and critical research and addressing discrimination and stigma.” The WFN, in collaboration with the International League Against Epilepsy, the International Bureau for Epilepsy, the International Child Neurology Association and European Federation of Neurological Associations, powerfully advocated for this resolution, actively participating in the 71st and 72nd WHA and the 146th WHO executive board meeting, where the historical decision to discuss a possible draft resolution on further action on epilepsy and other neurological disorders had been made.

Notably, WFN actively supported the WHO actions aimed on prevention and treatment of non-communicable disorders, and, indeed, productive collaboration with the WHO strengthened the Global Neurological Alliance.

As the WFN trustee, I have been deeply involved in the WHO COVID-19 NeuroForum and NeuroResearch Coalition, co-chairing the WHO NeuroForum follow-up and long-term impact working group, which meaningfully contributed to the creation of the WHO Case Report Form for Post-COVID conditions and is working on several important projects on prevention and care of patients with its neurological manifestations.

I worked in the WFN Membership Committee, communicating with several neurological societies, and bringing them closer to the WFN as the potential new members. I was privileged to contribute actively to the WCN.

I feel very much honored to be nominated for the re-election. During my term as WFN trustee, I have become aware of both the exciting opportunities as well as the significant challenges facing the global neurological community. If re-elected, I will continue to serve faithfully to the WFN, working diligently, fostering partnership with national, regional, and international neurologic societies and disease-based organizations, further developing collaboration with the WHO in order to assist the WFN to achieve its mission to improve neurological care, education, and research worldwide. •

Candidate Statements for First Vice President

Riadh GouiderRiadh Gouider

I trained at the Charles Nicolle Hospital in Tunis, and in La Pitié Salpêtrière Hospital in Paris. This mixture of learning and training encouraged me to explore global neurology.

My journey with the World Federation of Neurology (WFN) began in 1993 during the 15th World Congress of Neurology (WCN) in Vancouver. Since then, my enthusiasm and commitment to WFN has never wavered.

Being the national delegate of the Tunisian Society of Neurology for almost a decade (2005-2015) showed me how important a delegate can be as a crucial link between his national society and the international neurology community.

Appointed as a regional director for Pan-Arab region from 2008-2010 and regional director Africa from 2012-2015 taught me the crucial role of the six regions in WFN strategy and actions, especially when the neurology resources are scarce.

To support the WFN in its mission to promote global neurological education and training, I participated in the accreditation of three teaching centers : Rabat, Dakar, and Cairo.

Lately, I had the honor to be designated as the convenor of the first WFN/AFAN e-Learning Day, which took place in October 2020, the second will be held in November 2021.

My involvement on several committees of WFN: as a co-chair of the e-Learning Task Force, the Education Committee, the specialty groups, and the e-Communication Committee, provided me with invaluable insight into those committees’ functions, the development of their activities, and their positions within WFN.

The most important influence was my election for two terms as an elected trustee from 2014 to 2020. This position filled me with a strong sense of pride and gave me the chance to significantly contribute to the challenges the WFN has faced and the opportunities to participate in the activities of the WCN meetings.

I have had the honor of serving the WFN through a variety of roles.

I feel that I am experienced and honored to stand for the role of first vice president.

If elected, I pledge to support the mission of the WFN to contribute to the advancement of teaching and practice of neurology throughout the world.

I will focus on:

– Provision of access to quality training programs and teaching materials to neurologists, trainees, and health care professionals from all over the world through the e-learning capabilities.

-Creation of more teaching centers all over the world, especially Africa, Central and Southeast Asia, Latin America, parts of Eastern Europe, providing equal educational opportunities in regions with fewer neurologists.

-Strengthening relations among south and north countries and be an active contributor to the dissemination of information and scientific progress.

To further empower and strengthen the links of communications between WFN and regional organizations.

Enhance the cooperation of WFN with international organizations such as the WHO and neurological NGOs.

My fellow delegates, I am asking for your vote to be elected as first vice president. Regardless the results of the election, I promise to continue working for the WFN with the same enthusiasm and commitment. •

 

Gustavo Román

I was honored by my nomination as candidate for vice president of the World Federation of Neurology (WFN) from the American Academy of Neurology and neurologists from Colombia, my homeland, Brazil, Chile, Honduras, Panama, Uruguay, Spain, and France.

My mentor, Prof. Charles Poser, who served as editor of World Neurology in 1960 instilled in me the importance of the WFN in a globalized world. Over four decades, I served two terms as elected trustee of the WFN and participated in numerous activities.

I was born in Colombia and as an intern encountered the challenges of neurologists working in tropical countries: confronting formidable diseases with minimal diagnostic tools and a limited therapeutic arsenal. With a scholarship, I studied at the Salpêtrière in France and learned the enduring value of clinical neurology and neuropathology. Back in Colombia, I was appointed neurology faculty and wrote two textbooks: Practical Neurology and Tropical Neurology.

I joined Texas Tech University as professor of neurology and interim chair of neurology. In 1990, I was appointed chief of neuroepidemiology at the National Institutes of Health (NIH). I published HTLV-1 and the Nervous System; contributed to the diagnostic criteria for vascular dementia and guidelines for epidemiological studies on epilepsy; I co-authored Neurocysticercosis: A Clinical Handbook and participated in a multinational study of epidemic neuropathy in Cuba. I chronicled this experience in the book Cuban Blindness: Diary of a Mysterious Epidemic Neuropathy.

I returned to teaching at the University of Texas San Antonio as professor of neurology, medicine (geriatrics), and geriatric psychiatry and established the Alzheimer Disease Clinic. In 2010, I was selected the “Jack Blanton Endowed Chair” to organize a new memory center at Methodist Neurological Institute where I currently serve as professor of neurology, Weill Cornell Medical College, New York, and Texas A&M College of Medicine.

At the beginning of the pandemic, in early 2020, as chair of the environmental neurology specialty group of the WFN, I proposed creating international neurological registries of COVID-19 among neurological societies worldwide (Lancet Neurology 2020;19:484). With the group, I wrote the first comprehensive review on the neurology of COVID-19 (J Neurol Sci 414 (2020) 116884). These efforts resulted in the formation of scientific groups, such as the global COVID-19 Neuro Research Coalition (Ann Neurol 2021;89:1059).

As vice president of the WFN, I pledge to continue addressing the needs of neurologists worldwide during this pandemic, with emphasis on education and accessibility to scientific information to better serve neurological patients. Nontraditional methods and creative solutions such as telemedicine that have proven effective during the pandemic may have myriad applications in regions of the world with few neurologists.

We must be ready for future challenges, and the WFN is the only institution capable of serving as link of union and coordinating core for neurologists around the world. As vice president, I pledge to advance the goals and mission of the WFN in forging the future of neurology around the world. •

 

Guy Rouleau

I am honored that the Canadian Neurological Society (CNS) has nominated me for the position of WFN first vice president.

Following medical school at the University of Ottawa, I did neurology training at McGill University and research training at Harvard (PhD 1989). I then began my career as a clinician-scientist at McGill. In 2004, I moved to the University of Montreal as director of research at Ste‐Justine Hospital. I returned to McGill in 2013 as chair of the department of neurology and neurosurgery, and director of the Montreal Neurological Institute-Hospital (MNI). My work focuses on genetic diseases of the brain, and I have published over 800 articles in peer‐reviewed journals and have been cited over 85,000 times.

I collaborate with neurologists from every continent. Among many other international activities, I co-organized two Congrès de Neuroscience du Mali à Bamako, and I lead a project in Shenzhen, China, assisting the development of advanced therapies for epilepsy and movement disorders. I initiated the WFN-Neurological Institute-Canadian Neurological Society Departmental Visit program for young South American neurologists. The MNI funds these visits and provides the training. We are organizing a similar program for young African neurologists. As Canadian delegate to the WFN for six years, I know the organization well. In that role, I helped the CNS make a successful bid to host the 2023 WCN in Montreal. As WFN first vice president, I would be ideally positioned to contribute to the success of this upcoming congress.

I hope to increase the WFN’s impact on the practice of international neurology. The advent of the internet, social networks as well as accelerated medical discoveries, bring rapid, constant change requiring that organizations regularly reassess their structures and modes of operation.

As first vice president, I would recommend establishing a task force to make recommendations about how to:

Modernize: Currently, the president is elected quadrennially. The past president has no official role, leading to a loss of experience and talent. To ensure continuity, most professional organizations have a president-elect, president, and past-president. This structure could be explored.

Democratize: We need to find ways to ensure that younger people are more engaged and better represented within the WFN. The WFN must be relevant to neurologists of all ages and professional stages. The gender balance and diversity in the WFN’s leadership must also be improved.

Open: The impact of the open sharing of information is growing and has been accelerated by the COVID-19 pandemic. Sharing of information in medicine must become the norm. The WFN should adopt the open science ethos to allow equal access to information, ensure transparency, reproducibility, and equity. Under my leadership, the MNI has become a world leader in open science. Experience and methods developed there can help the WFN facilitate the spread of open science in the world of neurology.

On a personal level, I have spent nearly 40 years practicing neurology. I remain fascinated by the work we do, and I feel I still have much to contribute to our field. •

Candidate Statements for President

Ryuji Kaji

For the cause of World Federation of Neurology (WFN) in this challenging time, it has been my privilege and pleasure to serve as the first vice president of the WFN during an unprecedented time of worldwide crisis caused by the pandemic, which has altered the way we conduct the business as the new normal. We are at a turning point in modernizing the structure and function of the federation to meet the new demands. I am proud to be nominated as a candidate for the office of president at this important juncture.

As a graduate from Kyoto University in 1979, I started my professional career as a neurologist studying in the U.S. as a clinical fellow at the University of Pennsylvania. After returning to Japan with my mentor, Prof. Jun Kimura, to teach at our alma mater, I first described the use of IVIG to reverse muscle atrophy in multifocal motor neuropathy, an ALS-like disease.

Encountering a patient with task-specific dystonia, while doing EMG, I became interested in movement disorders, and our group has found new genes causing dystonia. In 2000, I was elected as a member-at-large for the International Federation of Clinical Neurophysiology (IFCN), which I served until 2006. I organized, with IFCN support, a symposium to develop a guideline for early diagnosis of ALS, now adopted as Awaji criteria (an island of Japan).

From 2006 until 2013, I was elected twice as a trustee of WFN under Prof. Aarli and Prof. Hachinski. First, I chaired the membership committee, successfully soliciting six new member societies. Second, I led Asia Initiative to vitalize Asian Oceanian Association of Neurology (AOAN), which now serves as a model of regional organizations in all continents with the help of Prof. Shakir. In 2017, I was elected as first vice president, and have since assisted Prof. Carroll in organizing the congresses and promoting the education of neurologists globally, a major thrust of WFN objectives.

If elected president, I would like to move forward on several initiatives. We must seek to achieve greater worldwide recognition of our discipline and make the prevention and treatment of neurologic conditions the No. 1 priority of governmental medical policies. Specifically, we should encourage and assist the education of young neurologists in developing countries. In undertaking these goals: I will abide by the basic mission of WFN to “foster quality neurology.”I will review the regional representations of trustees to make all the continents fairly represented with the best use of co-opted positions. I will make the regional liaisons stronger by closer contacts with the presidents and delegates of our member societies.

I have learned from the fellow trustees how to accomplish the best consensus with proper balance of assertion and compromise. I believe that it will take a team effort to successfully run an international organization. It is my sincere hope that together we can achieve our objectives and further improve the value and prestige of WFN. •

 

Wolfgang Grisold

I would like to apply for the position of the president of the WFN.

Having served as the secretary general of the WFN for the past eight years, I have gathered knowledge on all areas of current and previous activity. I designed and organized several initiatives, and made substantial contributions to WFN’s growth as a globally operating organization. Based on countless conversations with representatives and insights I have gained, I am convinced that my agenda for the presidency meets the needs of the WFN and its membership. My proposed agenda revolves around three key goals.

The first is to intensify the collaboration of all WFN members across countries and regions. Neurological diseases are becoming increasingly prevalent throughout the globe and neurologists are at the forefront to solve the great challenges of our time. As our members bring in distinct strengths and competencies, we can jointly advance the treatment of illnesses and our patients’ well-being. A cornerstone of my presidency will be to strengthen collaboration with WHO, the global neurology network, and scientific societies to successfully advance our initiatives.

My second goal is to increase the impact of the WFN. As per our mission, we strive to enhance high-quality neurology and brain health worldwide. Our focus is to make neurology accessible in all parts of the world and for all patients in need. To this end, I see high-quality education as the backbone as it empowers regions to consolidate, advance and adapt their education and treatment strategies.

Among other activities, I intend to drive the development of training centers and department visits, integrating  emerging opportunities of virtual education. I am confident we can increase our impact by training and empowering aspiring neurologists. My plan is to design a global training charter to establish standardized neurology training, and establish fellowship, advocacy, and leadership programs.

My third goal is to ensure coherence and continuity. The WFN has launched several successful initiatives targeting all aspects of brain health. One prominent example is World Brain Day, which has significantly helped raise public awareness about neurological diseases. We are fortunate to launch new initiatives and programs, but can only make a sustainable impact where there is continuity and coherence across projects.

One way to increase coherence and continuity is to smooth transitions between administrations. I envision the immediate past-president and president-elect serving in overlapping periods to ensure an efficient, transparent handover.

Importantly also, I will endeavor to balance the gender distribution in leadership roles and give patients a voice in WFN.

I am applying for the presidency of the WFN because I see many promising opportunities that we can achieve together over the next four years. At the heart of my agenda is the will to “strengthen the strengths” of our organizations and further improve outreach and impact of our programs for neurology and neurological patients.

It would be my sincere pleasure to work with you on these programs in the next four years. •

 

Youssef Al-Said

As the current Saudi Neurology Society President (SNS), it would give me great pleasure and be an honor to represent the World Federation of Neurology (WFN) and therefore am submitting my name as a nominee for the position of president.

As an experienced senior professional in neurology and epilepsy, administrative MBA graduate and the executive director of medical and clinical affairs at one of the leading hospitals in Saudi Arabia, I believe I embody the vision and mission of WFN on a daily basis to raise professional and academic proficiency in neuroscience.

My goal is to always lead with movement to action through results-oriented execution. Using this kind of leadership,neuroscience will reach new heights within the kingdom and see real time results.

Neuroscience is not just my career; it is my passion, and I would like to continue to share my knowledge with those entering in the field and contribute to the development of our youth as well as expand and improve the services throughout the kingdom and worldwide.

This year, 2021, is a year of inspiration as we transform to a new norm. Let’s go forward and try to reach a brighter future.

In closing, it would be a pleasure to be considered as the president so that I may help lead from the front as an action-centered leader for neuroscience.

I look forward to hearing from you. •

Eight Years of Experience in Training African Neurologists in Rabat

By Prof. Mustapha El Alaoui-Faris, WFN Rabat Training Center

Mustapha El Alaoui-Faris

Mustapha El Alaoui-Faris

After the accreditation of the Rabat Training Center in September 2013, the WFN signed a contract with the Mohammed V University of Rabat to train neurologists from Sub-Saharan Africa in Morocco. It was decided to start with complementary training in clinical neurophysiology for neurologists who have already completed their studies. They receive a grant of 13,000 Euros from the WFN covering travel and living expenses in Rabat for 10 months. The internship includes training in the performance and interpretation of EMG and EEG and in the management of patients suffering from neuromuscular diseases or epilepsy.

During their training, neurologists participate in the various teaching activities of the Department of Neurology of Rabat and attend the meetings of the Moroccan Society of Neurology in Morocco and in the Maghreb. Neurologists from Burkina Faso, Chad, Guinea, Madagascar, Mali, and Senegal have benefited from this training, which has allowed them to consolidate their EMG and EEG practices. In this regard, I would like to thank Prof. Reda Ouazzani, head of the clinical neurophysiology department, and his team, in particular Prof. Nazha Birouk, for their commitment and their availability during the African neurologists’ internship.

During the eight years of training for French-speaking African neurologists, the Rabat Center has received eight diligent trainees committed to expanding their knowledge and improving their expertise. They all have a good knowledge in general neurology, whatever their country of origin. This is due to the heritage of excellence of the French neurological school in these countries.

Currently, 14 French-speaking countries organize training of neurologists on-site, but due to lack of financial resources, they only train one to five neurologists per cohort. At this rate and given the glaring lack of neurologists in sub-Saharan Africa (barely 0.03 neurologists per 100,000 inhabitants, whereas the WHO calls for 1/100,000), it would take decades to reach a sufficient number of neurologists in these countries.

It is therefore important to explore the different possibilities to increase the number of neurologists in sub-Saharan Africa, while being aware that the majority of African neurologists trained in Europe and North America do not return to their countries.

Currently, the WFN has four accredited training centers in Africa, each center receives approximately one neurologist per year, often for additional training. Alternatively, neurologists can be trained in their own countries with the possibility that the last year of training be done in a training center approved by the WFN in Africa. This might be cost-effective for French-speaking African countries with good neurology training centers and affordable costs of living.

At the Rabat Center, we are willing to provide full training in neurology (4 years), in addition to continuing the annual training in clinical neurophysiology sponsored by the WFN and by the ICNMD Congress.

To ensure continuing education of French-speaking neurologists, the WFN in collaboration with the African Academy of Neurology (AFAN) can organize virtual courses in neurology in French. The courses could be made available on the WFN website. The lack of neurologists in Africa will not be filled any time soon, so it would be desirable in the era of video conferences that the WFN could provide education on “neurology for non-neurologists” for general practitioners in sub-Saharan Africa.

Finally, to accelerate the training of African neurologists, it would be desirable for the WFN to develop a true “Alliance for Neurology in Africa” by involving the AAN, the EAN, and other partners of the World Brain Alliance for its financing. This will improve the care of millions of African patients suffering from neurological disorders. •

Tour Through the WFN Continues

The Finance Committee and the Specialty Group on Neuroepidemiology

By Wolfgang Grisold

Wolfgang Grisold

Wolfgang Grisold

In this issue of World Neurology, we would like to continue to introduce you to one committee and one specialty group. The committee/specialty group is introduced by the respective chairs, who were asked to explain their tasks and activities to our membership. Further details, such as the list of committee/specialty group members can be found on the WFN website, as well as email addresses of the chairs and members, which will be helpful if you want additional information.

The Finance Committee

Bo Norrving

Bo Norrving

The Finance Committee is chaired by Prof. Bo Norrving. He is senior professor in neurology and a consultant neurologist at Lund University Hospital in Sweden. He has been active in several functions in the WFN oven many years. He has a long experience in governance and leadership of scientific societies, including being president of the World Stroke Organization.

The Finance Committee has several experienced members with a global representation. The task of the WFN Finance Committee is to regularly review the economic strategies and financial situation of the WFN, functioning as an independent body from the WFN executives. The Finance Committee identifies strengths, weaknesses, opportunities, and threats for the WFN, and tries to look into the future taking the global economic situation, and environmental and political issues into account.

The committee also considers the need for adaptations of WFN educational and training activities related to information technology issues, educational tools, and practical issues. The committee helps to ensure that the WFN has a strategy to maintain an economic corpus that is a sufficient reserve for any upcoming disruptions and other threats. In particular, it is essential to have a sustainable balance to support future core projects (fostering best neurological practices, education, and research) and maintaining reserves in case of a downturn in congress income in the future. For this purpose, the assets are composed of short- to medium-term working capital and a longer-term reserve fund. WFN finances and corporate structure are regularly audited.

Over the years, the views of the Finance Committee and those of the trustees have been in excellent agreement. The committee acknowledges the careful strategic planning that has been in constant function at the WFN leadership over the past decades and continues into the future.

Specialty Group on Neuroepidemiology

Carlos N. Ketzoian

Carlos N. Ketzoian

The Specialty Group on Neuroepidemiology is chaired by Prof. Carlos N. Ketzoian, neurologist, epidemiologist, and neurophysiologist from the Neuroepidemiology Section, Institute of Neurology, University Hospital, School of Medicine, Montevideo, Uruguay. (carlosk@mednet.org.uy). He has been chairing and researching in several neuroepidemiology activities, is the past-president of the Pan American Society of Neuroepidemiology, and participates in national and international scientific activities. He is also a member of the editorial board of neuroepidemiology.

The Specialty Group on Neuroepidemiology has a long history in the WFN. The proceedings of the group are oriented toward activities of teaching, research, and presentation of neuroepidemiologic results in academic activities, either in the congresses of the WFN or in congresses in different regions such as the Pan American Congresses of Neurology and Pre-Congress Symposia organized by the Pan American Society of Neuroepidemiology.

At the WCN 2021, a scientific session on neuroepidemiology will take place themed “The impact of socio-demographic, economic, and cultural factors on the epidemiology of neurological disorders (WFN Specialty Group on Neuroepidemiology)” on Oct. 6, 2021, in Rome, which is now a virtual meeting.

Research courses and projects have been developed for low- and middle-income as well as high-income countries, favoring a North-South interaction and collaboration. This has had a positive impact on the training of human resources in the area of neuroepidemiology.

Future projects will offer neuroepidemiology training activities in low-income countries. The II Latin American Neuroepidemiology Course scheduled for March 2020 has been postponed without a still-confirmed date of completion given the COVID-19 pandemic global situation. The current situation will need adaptation and virtual as well as hybrid courses will need to be implemented. •

Prestigious WFN Medals Announced

These medals will be awarded at World Congress of Neurology 2021.

WFN Medal Service to International Neurology
Prof. Vladimir Hachinski

WFN Scientific Achievement in Neurology
Prof. Jerry Mendell

WFN Meritorious Service Medals
Prof. Donna Bergen and Keith Newton

Munsat Prize for Service to Education
Prof. Erich Schmutzhard

 

 

A Neurology and Psychiatry Clinic in Central America

With Suggestions for Starting a Clinic

By Lawrence Robbins, MD

Neurology/psychiatry clinic near Tegucigalpa, Honduras.

Neurology/psychiatry clinic near Tegucigalpa, Honduras.

Starting the Clinic: The clinic is located within an excellent rural medical center near the main city (Tegucigalpa). Associating with an established medical center has been ideal. Ninety-five percent of the population has no access to neurology or psychiatry. I decided that it was crucial to supply various neurology and psychiatry medications. Locating the clinic relatively close to a big city was important. Close access has allowed me to teach in the public hospital, bring in other physicians, and refer patients for tests, Suggestion: Look for an established, well-run clinic, and locate within proximity to an international airport. This may not be feasible in all locations.

Associating With an Organization: It is difficult to start a clinic completely independently. I have had a close association with a well-established organization that runs our medical center. They provide room and board, and also help with security, transportation, and hiring clinic personnel. Suggestion: If possible, find community support. Establish close ties with an organization as there are many benefits.

Funding: Alas, it takes money. Lots of it. The plan was to establish a not-for-profit, which I did. With more resources, I was able to build out infrastructure, supply additional medications, and hire extra staff. Fundraising is important, but is one of the most difficult aspects of the venture. I am lucky to have a number of generous donors. Suggestion: If possible, start a nonprofit organization. This is vital for fundraising.

Staff of the neurology/psychiatry clinic.

Staff of the neurology/psychiatry clinic.

Personnel: I began with myself, one chart, and one patient. Over time, we have added two psychiatrists and two neurologists, a nurse administrator, and a psychotherapist. We pay the staff approximately what they would make working in their own private practice. The Honduran physicians are young and idealistic. Networking in neurology and psychiatry circles within the country helped me to connect. Connecting with the local neurology/psychiatry societies has been helpful. Neurologists and psychiatrists are in relatively short supply. The Honduran physicians are excellent, but often underpaid. I occasionally bring in another physician from the United States with me. This is usually a rewarding experience. The nurse administrator is a major key to success. The nurse administrator handles recruitment of patients, scheduling, managing patients in the clinic, medications, and other tasks. Suggestion: An administrator, preferably a nurse, is an invaluable part of the team. The downside of bringing in other physicians, or other personnel from another country, is that you are (somewhat) responsible for their trip and safety.

Charting: We are on paper charts, which is easy, and we keep a medication flow sheet. Our paperwork is minimal. Some notes are in English (mine), most are in Spanish. Since we treat each other’s patients, it helps if we list our thoughts for future considerations. In the beginning, we did not need medication or diagnosis flow sheets, as there were only one or two notes to review. Over time, after 15 or 20 visits, the need for flow sheets becomes apparent. Suggestion: Try to keep medication and diagnoses flow charts. It is beneficial to develop uniform charting, as multiple providers may be treating the patient.

Clinic Infrastructure: We have built out a neurology and psychiatry suite, along with a small pharmacy. If our budget were smaller, we would share space with the medical center, and minimize testing. We have supplied computers, and installed internet capability. The internet (usually) works, allowing me to research various conditions that I encounter. Books are convenient to store on my phone or laptop. However, it is more efficient to actually have the physical book handy. Suggestion: It is helpful to have a section of the pharmacy dedicated to the neurology clinic. Internet capability is extremely useful.

Recruiting Patients: In our clinic, the nurse administrator is in charge of recruitment. We have informed various medical clinics of our existence. We also placed a number of public service ads on radio. The neurologists and psychiatrists in nearby cities refer patients. Eventually, word of mouth drives most of the new patients. We draw patients from the entire country and surrounding countries. Suggestion: By alerting other clinics of your neurology clinic, word of mouth spreads quickly. It is helpful to let other physicians know about the existence of the clinic.

Our Services: Our primary purpose is to provide diagnosis and treatment for the vast underserved population. In addition, we offer free medications. We provide free blood tests and EEGs as well. Much needed psychotherapy services are offered on a limited basis. Psychotherapists are difficult to come by. In some settings, a layperson may be trained to be an “active listener.” We have run into barriers with providing therapy services. These barriers include stigma, reluctance to divulge personal information in a rural community, and lack of therapists. We provide patients with a safe place and offer emotional support. We are usually patients’ sole access to care. Suggestion: If possible, supplying medications is invaluable. If therapists are not available, training lay people is a possibility.

Medications and Pharmacy: The basic meds we provide include: antidepressants, anticonvulsants, mood stabilizers, migraine meds, and Parkinson’s medications. I decided that levetiracetam would be a mainstay. It is safe and does not require blood tests.

Our small neurology/psychiatry pharmacy is kept locked at all times. Suggestion: Choose medications that are relatively safe and do not require blood tests. If you purchase medications locally, you can often negotiate a better price.

Telemedicine: Since we have equipped the clinic with internet access, we have been able to connect remotely. Technically, it is a bit cumbersome. I am in Chicago with an interpreter but no chart, and the patient sits in Honduras with a nurse. The lack of insurance (and other) paperwork is helpful. These visits are not ideal, but better than no access at all. Suggestion: Telemedicine can work if there is adequate internet access.

Tests: Lab, MRI, EEG, etc: We do a limited number of blood tests. These tests are relatively expensive in Honduras. We are performing 20 EEGs on a monthly basis out of our clinic. This has been extremely helpful, as many epilepsy patients have not had an EEG, or any access to neurology. MRI/CT is expensive and not easy to obtain. However, many patients do pay for their MRI (about two weeks’ salary) and they bring in the films. We try to use as little testing as is feasible. Suggestion: Blood tests are important, and negotiating a better price is worthwhile. Diagnosis and treatment are often determined without advanced imaging.

Emergencies: We occasionally have a patient in status epilepticus or other neurologic emergencies. I am available from the U.S. for advice. WhatsApp works the best for remote communication. We stock the Emergency Room with basic medications (eg, fosphenytoin and diazepam for seizures). There is a Public Hospital in the main city, but transporting patients there is an adventure. There is only one local ambulance, and we need permission to use it. Suggestions: Neurologic advice often proves invaluable to the ER doctors. It helps to provide basic neurologic emergency medications.

Teaching/Publications/Videos: I teach neurology and psychiatry residents in Tegucigalpa. We have written a manual in Spanish on management of headache. This manual was distributed to many of the Honduran physicians. Suggestion: Teaching the local physicians is a rewarding experience. Articles document your experience and may spur others to follow your path. Videos of the clinic bring the clinic and patients to life. The videos can be instrumental for fundraising and promotion.

Acknowledgements: It takes a number of people to make this clinic a success. Our incredible donors have provided the crucial funding All of the personnel in SAN (Honduras) have provided vital support. The Honduras clinic staff and doctors are the mainstay. •

Lawrence Robbins, MD, is an assistant professor of deurology at Chicago Medical School. Lrobb98@icloud.com; Chicagoheadacheclinic.com (Honduras Project Section with videos/blogs)

Neurology Update in Kazakhstan 2021

By Aida Kondybayeva, MD, PhD

Aida Kondybayeva

Aida Kondybayeva

The International Educational Online Forum: Neurology Update in Kazakhstan was held April 23-24, 2021. Forums of this scale in Kazakhstan are held every two years, and this forum was being held online for the first time. The event was attended by 985 doctors, including neurologists, internists, GPs, rehabilitation specialists, and intensive care specialists from Kazakhstan, Kyrgyzstan, Uzbekistan, Belarus, and Ukraine.

At the first day within the framework of the International Educational Online Forum: Neurology Update in Kazakhstan, the EAN-Day in Kazakhstan was held. This event was held with the joint work of the European Academy of Neurology, Kazakh National Association of Neurologist Neuroscience, and al-Farabi Kazazakh National University.

Welcoming speeches to the participants were given by Prof. Saltanat Kamenova, president of KNANN; Nadezhda Petuhova, chair of the Public Council of the Ministry of Health of the Republic of Kazakhstan; Prof. Raushan Isayeva, director of High School of Medicine, Faculty of Medicine and Health, al-Farabi Kazazakh National University; and Mikhail Mazurchak, vice president of KNANN. They noted the special significance of the EAN-Day in Kazakhstan for all practicing doctors who took part in this event.

The speakers of the EAN-Day in Kazakhstan were Prof. Aksel Siva from the Department of Neurology of Istanbul University, Cerrahpaşa School of Medicine (Istanbul Turkey); Prof. Erik Taubøll from the Department of Neurology Oslo University Hospital (Oslo, Norway); and Prof. Maxwell Simon Damian, Department of Medicine, Cambridge University (Cambridge, UK).

The professors presented reports on the situation with MS, epilepsy, and neuromuscular diseases before and during the COVID-19 pandemic; these presentations aroused great interest among all participants of the event.

Luca Caffaro, the youngest speaker of this event, presented an interesting report on the work of the Residents and Research Fellows Section (RRFS) of the EAN, and on professional development opportunities for young neurologists and residents. EAN-Day in Kazakhstan received positive feedback from all registered participants of the event.

In the second half of the event, workshops were held, in which speakers presented analyses of difficult clinical cases and the possibilities of their resolution. The second day, the forum was no less eventful, and included reports of doctors from Spain (Jerzy Krupinski-Bilecki), Afghanistan (Ayesha Khaideri), Ukraine (Sergey Moskovko), Russia (Dmitry Kasatkin, Evgeny Evdoshenko, and Natalia Khachanova), and Kazakhstan (Gulsum Duschanova, Saltanat Kamenova, Gulnar Kabdrakhmanova, Mikhail Mazurchak, Maksharip Martazanov, Karlygash Kuzhibaeva, Aida Kondybayeva, and Asel Aralbayeva). Topics including MS, pain, neuromuscular diseases, and epilepsy were discussed. •

Aida Kondybayeva, MD, PhD, is a neurologist and chair of the Educational Committee at Kazakhstan National Association of Neurologist “Neuroscience” Institutional Delegate of the European Academy of Neurology from Kazakhstan.

 

Cerebral Venous Thrombosis After Vaccination Against SARS-CoV-2

With Information on the International Consortium on CVT Registry

By José M. Ferro, MD, PhD

The public and the global medical community have been exposed since early March 2021, both from the media, the official agencies, and the medical literature, to multiple and often contradictory information, concerning the risk of “uncommon” thrombosis occurring after vaccination against SARS-CoV-2. Most of the news concerned the vaccine manufactured by AstraZeneca and more recently the vaccine from Johnson and Johnson/Janssen. The uncommon thromboses were splanchnic and cerebral venous thrombosis (CVT), mostly the latter.

Mass vaccination is currently humanity’s great hope to control the pandemic. Vaccines were developed, tested, and approved in an incredibly fast pace, about one year since the onset of the pandemic. Administration of a vaccine simultaneously to millions of persons in multiple locations of the world was never done before in human history. Not surprisingly, extremely uncommon side effects of the vaccine, which were not detected in randomized trials of hundreds or thousands of subjects, can emerge when a much larger sample of millions is exposed to the vaccine.

COVID-19 Infection and CVT

CVT was known to occur as a rare complication (0.08%) of COVID-19, accounting for 4.2% of all acute cerebrovascular disease occurring during COVID-19 infection. Several case reports, case series, and systematic reviews of CVT associated with COVID-19 infection have been reported since the beginning of the pandemic 1,2. Both a systematic review2 and a large study based on administrative data from a hospital network3 indicate than the incidence of CVT increased with COVID-19 infection.

CVT can be the initial clinical manifestation of the infection, but the majority of CVTs develop within 13 days of onset of COVID-19 symptoms. Recognized risk factors for CVT are present in only one third of the patients. The main pathophysiological mechanism is related to the hypercoagulable state seen in moderate/severe COVID-19 disease. In fact, CVT patients often have very high D-Dimers, low fibrinogen levels, and low platelet counts. The prognosis is less favorable; namely case fatality (40%) is higher than the non-COVID-19 CVT (5-10%). Management is similar, namely on what concerns the use of parenteral heparin in the acute phase of CVT.

Case Reports and Case Series of CVT Occurring After Vaccination Against SARS-CoV-2

The European Medicines Agency (EMA) approved four vaccines against SARS-CoV-2: two mRNA vaccines from Pfizer and Moderna and two adenovirus vector DAN vaccines from AstraZeneca (AZ) and Johnson & Johnson/Janssen (JJ). The AZ vaccine is not yet approved for use in the United States.

Shortly after the onset of mass vaccination with those vaccines in Europe and in several other countries around the world, there were signals and thereafter publications of case reports and small case series of severe CVT occurring in young women within days of vaccination with the AZ vaccine 4-8. The growing number of those events led several countries to contraindicate the AZ vaccine in young and middle-aged adults, despite the total number of signaled cases being low (<200) as well as the estimated absolute risk of CVT (5 per million vaccinated individuals). In April, a small number of similar cases were reported in the U.S. after the JJ vaccine 9, leading the authorities to temporarily pause the use of that vaccine. A few individuals developed immune thrombocytopenia (ITP) 10 without thrombosis after receiving the mRNA vaccines. There are a few CVTs also reported, but the percentage of CVT occurring after mRNA vaccination is much smaller than for the adenovirus vector DNA vaccines

A striking feature of those cases was the high frequency of thrombocytopenia, which is uncommon in pre-COVID-19 CVT (<10% of the cases). Some other patients had only thrombocytopenia, splanchnic venous thrombosis, or hemorrhagic phenomena, or a combination of those, eventually with CVT. Although most of the emphasis has been placed in the thrombocytopenia, the most serious event, which may be fatal, is CVT. CVT is obviously also the most relevant event to the neurology community.

From the published cases and those signaled to the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), a clinical profile of CVT associated with the AZ vaccine can be extracted:

  • CVTs occur almost exclusively in women below age 60.
  • Only about one third has traditional risk factors for CVT, such as thrombophilia or use of estrogenic contraceptives.
  • CVT occurs up to 20 days after the administration of the first dose of the vaccine.
  • A high percentage (up to two thirds) has thrombocytopenia; some have high D-Dimers and low fibrinogen.
  • The clinical picture is often of a malignant CVT, with multiple sinus and veins thrombosis, cerebral hemorrhages and oedema, causing herniation, often requiring decompressive craniectomy, as a live-saving intervention.
  • The mortality is high (~25%).
  • Patients with traditional risk factors for CVT do not appear to have an increased risk of CVT after vaccination.

Possible Pathophysiological Mechanisms

Chance association or undetected recent COVID-19 infection are possible, but unlikely, explanations for CVT occurring after AZ and JJ vaccines. They cannot account for the different risk of CVT after each type of vaccine, not for the distinct clinical laboratory profile, as described in the previous section. Moreover, SARS-CoV-2 PCR nasopharyngeal swabs were negative in all the patients, in whom that test was performed (or reported to be performed), and patients only displayed antibodies against the virus spike protein antigen (most probably a vaccine effect) and not against other antiviral antibodies, as expected if they were recently infected.

Shortly after the notice of the first cases of venous thromboses with thrombocytopenia, a group of researchers from Germany, Ontario, and Vienna under the leadership of Andreas Greinacher identified the mechanism of the thrombotic complications of AZ vaccine, which they called “thrombotic thrombocytopenia.” Unfortunately, this label underscores the fact that the main feature of the syndrome is CVT, with the consequent risk of death and disability. Their patients tested positive on a screening platelet factor 4 (PF4)-heparin immunoassay. None of the patients had received heparin before blood for the tests was drawn. Patients also tested positive on a platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin and immunoglobulin4. They concluded that the vaccine resulted in a rare thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia (HIT). In recent years, it has been recognized that triggers other than heparin (polyanionic medications, infections, surgery) can also cause a HIT-like coagulopathy, which can also be spontaneous. The pivotal observations of Greinacher et al 4 were confirmed by other researchers11. This post-vaccinial entity is now named vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) or vaccine immune thrombotic thrombocytopenia (VITT).

A similar laboratory observation was found in the cases reported after the JJ vaccine. This finding raises the suspicion that the adenovirus vector could be the initial trigger of antibody production. The adenovirus vector carries negatively charged DNA, which binds to the positively charged PF4. An alternative explanation is the strong inflammatory stimulus of the vaccination or cross-reaction of antibodies produced by the vaccine and PF44. RNA is charged positively, so this immune response is unlikely to occur after mRNA vaccines.

Management of Cerebral Venous Thrombosis Occurring After Vaccination Against SARS-CoV-2

The risk of CVT following AZ vaccine being estimated as only five cases per million vaccinated people, it is evident that no randomized trials are possible to inform management decisions. Evidence comes from case series, analogy with HIT management, and expert consensus statements, and therefore is of low quality. Strong recommendations are not possible and the most sensible option is to produce guidance documents that will be periodically updated, as new evidence is produced.

Vaccinated persons should be informed that they may experience a transient headache a few days after vaccination. If the headache persists or is unusually severe, or they have any other neurological symptom, they should seek urgent medical advice. These patients should be examined by a neurologist.

If the clinical picture is suspicious of CVT, cerebral CT with venography or MR with MR venography should be performed to confirm, or not, the diagnosis of CVT. Meanwhile, a complete blood cell count and film, coagulation tests (INR, APTT, fibrinogen, D-Dimers) and COVID antibodies are obtained.

If CVT is confirmed and platelet count is below 150×109/L, VITT is a possibility. However, if the results of coagulation tests, fibrinogen, and D-Dimers are normal, VITT is unlikely, and the patient can be managed accordingly to the current CVT Guidelines12, namely be treated with low molecular or unfractionated heparin in the acute phase.

On the contrary, if any of those tests is abnormal, VITT is suspected and a HIT Elisa test (capable of detecting PF4 antibodies) should be performed. Consultation with a hematologist is advisable to guide on further testing (e.g., functional HIT assays) and discuss management. Meanwhile, platelet transfusions should be avoided, IV immunoglobulin (e.g., 1 mg/kg for 2 days) be administered, and a non-heparin anticoagulant (argatroban, danaparoid, or direct oral anticoagulants) be used instead of heparin4,11. Endovascular treatment of CVT can also be an option.

The International Consortium on CVT Initiative

From the available evidence so far, it is apparent that CVT after SARS-CoV-2 vaccines can be a heterogeneous group of patients. While most appear to have an immune mechanism (VITT), a few other cases may be coincidental, related to the usual CVT risk factors or even to recent COVID-19 infection. Therefore, a detailed analysis of non-selected CVT cases who developed after any COVID-19 vaccination needs to be performed.

The International Cerebral Venous Thrombosis Consortium (ICVTC) is an existing, global collaboration by academic researchers with the primary aim to perform investigator-initiated research on the epidemiology, manifestations, and outcome of patients with CVT.

Currently, 32 hospitals are participating in the consortium and have already collected data of 1,308 patients with CVT, prior to the COVID pandemic. ICVTC recently launched a prospective registry to report clinical manifestations, laboratory findings, management and outcome of patients with CVT after any COVID-19 vaccination. The registry will include CVT patients with radiologically confirmed CVT, with onset of CVT symptoms within four weeks of COVID-19 vaccination, and informed consent. Principal investigator is Jonathan Coutinho from the Amsterdam University Medical Centers (j.coutinho@amsterdamumc.nl).

Conclusion

Medicine should follow the ethical principle of “Primum non nocere” (first do not harm). However, ethics should also be applied with justice. We must consider that the individual risk of CVT following COVID infection is much higher (6x) than that following any anti-SARS-CoV-2 vaccine3, even without considering the indirect effect of the infection through contagium. Therefore, the fundamental message for the public should focus on the urgent need, safety, and confidence on vaccines.

Epidemiological, clinical, and laboratory research will unveil the multiple remaining unanswered questions on the occurrence of CVT after anti-SARS-CoV-2 vaccines. Meanwhile, neurologists and other health care workers must be aware of this very rare complication of the AZ and JJ vaccines. Management of the occasional CVT patient occurring after those vaccines should follow the most recent guidance statements from national13 and international official agencies and from scientific societies14, which are likely to be updated as evidence grows. Inclusion of those cases in the ongoing International Consortium on Cerebral Vein Thrombosis registry is welcome. •

From the Serviço de Neurologia, Centro Hospitalar Lisboa Norte; J Ferro Lab, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa; Lisboa, Portugal. jmferro@medicina.ulisboa.pt

Inclusion Criteria for the International Consortium on CVT Registry

Patients with cerebral venous thrombosis with:

  • Radiologically confirmed CVT
  • Onset of CVT symptoms within 4 weeks of any COVID-19 vaccination
  • Informed consent, according to local law

For more information, contact Dr. Jonathan Coutinho at j.coutinho@amsterdamumc.nl.

 

References

  1. Dakay K, Cooper J, Bloomfield J, Overby P, Mayer SA, Nuoman R, Sahni R, Gulko E, Kaur G, Santarelli J, Gandhi CD, Al-Mufti F. Cerebral Venous Sinus Thrombosis in COVID-19 Infection: A Case Series and Review of The Literature. J Stroke Cerebrovasc Dis. 2021 Jan;30(1):105434. doi: 10.1016/j.jstrokecerebrovasdis.2020.105434
  2. Baldini T, Asioli GM, Romoli M, Carvalho Dias M, Schulte EC, Hauer L, Aguiar De Sousa D, Sellner J, Zini A. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol. 2021 Jan 11:10.1111/ene.14727. doi: 10.1111/ene.14727
  3. Taquet M, Husain M, Geddes JR, Luciano S, Harrison PJ. Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine. In press
  4. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840
  5. Castelli GP, Pognani C, Sozzi C, Franchini M, Vivona L. Cerebral venous sinus thrombosis associated with thrombocytopenia post-vaccination for COVID-19. Crit Care. 2021 Apr 12;25(1):137. doi: 10.1186/s13054-021-03572-y
  6. Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, Wiedmann M, Aamodt AH, Skattør TH, Tjønnfjord GE, Holme PA. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104882
  7. Mehta PR, Mangion SA, Benger M, Stanton BR, Czuprynska J, Arya R, Sztriha LK. Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination – a report of two UK cases. Brain Behav Immun. 2021 Apr 12:S0889-1591(21)00163-X. doi: 10.1016/j.bbi.2021.04.006
  8. Muir K-L, Kallam A, Koepsell SA, Gundabolu K. Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination. N Engl J Med. 2021 Apr 14. doi: 10.1056/NEJMc2105869.
  9. Franchini M, Testa S, Pezzo M, Glingani C, Caruso B, Terenziani I, Pognani C, Bellometti SA, Castelli G. Cerebral venous thrombosis and thrombocytopenia post-COVID-19 vaccination. Thrombosis Research (2021), https://doi.org/10.1016/j.thromres.2021.04.001
  10. Lee EJ, Liu X, Hou M, Bussel JB. Immune thrombocytopenia during the COVID-19 pandemic. Br J Haematol. 2021 Apr 14. doi: 10.1111/bjh.17457
  11. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, Goldblatt D, Kotoucek P, Thomas W, Lester W. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 16. doi: 10.1056/NEJMoa2105385.
  12. Ferro JM, Bousser MG, Canhão P, Coutinho JM, Crassard I, Dentali F, di Minno M, Maino A, Martinelli I, Masuhr F, Aguiar de Sousa D, Stam J; European Stroke Organization European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European Academy of Neurology. Eur J Neurol. 2017 Oct;24(10):1203-1213. doi: 10.1111/ene.13381
  13. Pai M, Grill A, Ivers N, et al. Vaccine-induced prothrombotic immune thrombocytopenia VIPIT following AstraZeneca COVID-19 vaccination: lay summary. Science Briefs of the Ontario COVID-19 Science Advisory Table. 2021;1(16). https://doi.org/10.47326/ocsat.2021.02.16.1.0
  14. Oldenburg J, Klamroth R, Langer F, Albisetti M, von Auer C, Ay C, Korte W, Scharf RE, Pötzsch B, Greinacher A. Diagnosis and Management of Vaccine-Related Thrombosis following AstraZeneca COVID-19 Vaccination: Guidance Statement from the GTH. Hamostaseologie. 2021 Apr 1. doi: 10.1055/a-1469-7481