The Online Mendelian Inheritance in Man (OMIM) Database

A useful genetic data repository for clinical neurologists.

Foreward by Martin Krenn, Department of Neurology, Medical University, Vienna, Austria

A large number of neurological disorders are characterized by a strong genetic component, either in a monogenic or a more complex polygenic sense. This is illustrated by the extensive portion of the human genome actively expressed in the central and peripheral nervous systems. Over the past decade, new genome-wide sequencing technologies have enabled us to identify single-gene etiologies in an increasing number of cases. More recently, these methods have also entered clinical routine diagnostics. As most of these conditions are very rare, the utilization of publicly available genetic databases is of utmost relevance for clinical neurologists to better understand human gene-disease relationships in neurogenetic disorders.

The Online Mendelian Inheritance in Man (OMIM) database offers a widely used, comprehensive, and constantly updated compendium of a vast number of monogenic (Mendelian) conditions. It is based on the most recent biomedical literature and thus constitutes a particularly useful resource for clinicians, often referenced in genetic diagnostic reports. It can be expected that the clinical value of such repositories will further increase in the coming years, as new neurogenetic disorders are still being discovered at a rapid pace, and more targeted treatments for patients are being developed.

The Online Mendelian Inheritance in Man

Cassandra Kniffin Arnold and Joanna Amberger

In 1863, Nikolaus Friedreich described a juvenile-onset form of hereditary ataxia (Friedreich ataxia). Several years later, George Huntington described an adult-onset hereditary chorea (Huntington disease). Nearly 100 years later, these familial genetic neurologic disorders, along with over 1,400 other genetic disorders, were included in Dr. Victor McKusick’s seminal textbook Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes (MIM). These catalogs were updated and published regularly, and in 1987, MIM was made freely available and searchable online as OMIMTM. Today, www.OMIM.org is a continuously updated, freely available compendium containing over 27,000 structured descriptions of human genetic disorders and genes. Currently, OMIM describes over 7,400 disorders caused by pathogenic variants in over 4,800 genes. On average, over 35,000 clinicians and researchers worldwide use OMIM daily to assist in disease gene discovery, clinical diagnosis, and management of genetic diseases, as well to understand the molecular bases of disease and the underlying medical science.

The information in OMIM is based on the peer-reviewed biomedical literature. Priority for inclusion in the database is given to published papers that provide significant insight into the phenotype-genotype relationship, expand our understanding of human biology, or contribute to the characterization of a genetic disorder.

Each OMIM entry (phenotype or gene) has a preferred title, with alternative names if relevant, and is given a unique 6-digit number that remains stable, even if the name changes. These OMIM accession numbers are used widely in publications and databases. OMIM entries are text-based and organized into consistent headings. Gene entries include information on gene structure, expression, function, animal models, and allelic variants, when available. Phenotype (disorder) entries include information on clinical features, inheritance, pathogenesis, genotype-phenotype correlations, and molecular genetics. In addition, each phenotype entry has an accompanying Clinical Synopsis, a concise tabular anatomical listing of the clinical features described in patients with the disorder. The relationship between phenotypes and genes is summarized in OMIM’s tabular Gene Map.

From its inception, MIM has played a foundational role in the nosology and naming of genetic disease.

In general, the naming and classification of disorders (phenotypes) in OMIM reflect that used in the respective medical community or as designated in the published paper(s).

OMIM curators evaluate reports of new phenotypes in the context of those present in the catalog and consider the following questions.

  • How many patients have been described in how many reports?
  • What shared features actually define the phenotype, and how thorough are the clinical descriptions?
  • Does this constellation of features represent a new entity?
  • Do the different features of a disorder constitute clinical variability of a single disorder or define separate disorders?
  • Have the same or similar features been described under a different name?
  • Is the phenotype similar to others in OMIM?
  • Can the phenotype be classified with any other disorders?

Answering these questions must also take into account the views and possible disagreements in the genetics community as well as published nosologies. Since the definition of a phenotype (constellation of features) as a genetic entity is an evolving process, the names of a disorder in OMIM may change over time, but an OMIM number remains stable. Disease names should be unique, enhance clinical care and classification, and be easy to communicate. Acronyms and eponyms can both serve in this capacity, although eponyms should be used sparingly. When disease names, designations, and classification schemes are not provided in the papers or are not agreed upon in the medical community, the process of disease naming and classification involves defining recognizable patterns of features and highlighting those that allow one condition to be distinguished from another. For new disorders, the three to five most clinically significant features are selected to create an acronym or initialism that is both informative and memorable. It may seem appealing to name a genetic disorder after a gene; however, this is not recommended for several reasons. Patients present with clinical features, and not all phenotypes have a recognized molecular basis. Importantly, many people around the world will not be sequenced and their conditions should be catalogued. Additionally, one-third of disease genes cause more than one phenotype, each with its own unique features, prognosis, molecular pathogenesis, and treatment. Phenotypes and genes are distinct concepts, and their names should change appropriately and independently to reflect greater knowledge. The OMIM number unifies clinical names and aliases under a single identifier.

If the same or similar phenotype exists in OMIM but that phenotype is caused by variants in a different gene, the existing name is used and a serial number is added at the end. These genetically heterogeneous phenotypes are then assembled into “Phenotypic Series” and given a unique PS accession number. Grouping similar phenotypes using clinical naming provides unique insights into molecular mechanisms and disease etiology, and offers a broader context for understanding the complexity of similar diseases. Examples of genetically heterogeneous neurologic disorders include Charcot-Marie-Tooth disease (CMT, PS118220), hereditary spastic paraplegia (SPG/HSP, PS303350), spinocerebellar ataxia (SCA, PS164400), and developmental and epileptic encephalopathy (DEE, PS308350). The clinical synopses of members in a Phenotypic Series can be viewed side-by-side on the website; such a view reveals differences that can guide physicians toward the right diagnosis and management or treatment. Each Phenotypic Series sheds light on shared molecular pathology and mechanisms of disease and/or can reveal new divergent avenues of investigation.

OMIM.org is freely accessible and is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. The entries have copious directed links to external resources including DNA and protein databases (GenBank, Ensembl, UniProt), clinical resources (genetic testing sites, ClinGen, Orphanet), genetic variant resources, (ClinVar, gnomAD), and animal model databases (Mouse Genome Informatics, OMIA). OMIM supports programmatic access to its content via an API (Application Programming Interface). Also available from OMIM.org is the service MIMmatch. MIMmatch is a way for a user to follow OMIM entries of interest and to find other researchers who may share interest in the same topics. Registered MIMmatch users are able to receive alerts about updates to genes and diseases of interest and/or receive notification of new phenotype-gene relationships added to OMIM. Help in using OMIM.org is available from the website with both written guides and short video tutorials.

For over 55 years, OMIM has chronicled the collected knowledge of the field of medical genetics and remains one of the primary repositories of curated information on both genetic disorders (phenotypes) and genes and the relationships between them. •

Cassandra Kniffin Arnold, MD, is senior medical writer, and Joanna Amberger is program manager at OMIM, Johns Hopkins University in Baltimore, Maryland. Dr. Martin Krenn, PhD, is from the Department of Neurology, Medical University of Vienna in Austria.

Placebo/Nocebo and the Brain

Toward a pharmacology and toxicology of words.

Placebo and recently the term nocebo are often used in situations where uncertain effects, possibly the effect of the mind works, and have been often disregarded as scientifical activities. All of us working with patients are implicitly using the concept of placebo, and sometimes the negative prediction, the nocebo.

As members of the health profession, we are part of placebo effect, and investigations have shown that also in regular approved and effective drugs a percentage of placebo effect can be calculated. The awareness of these important effects are important. The perception of placebo effect can in several instances be blocked or denied by cultural practices, and for neurology, it is important to spread and enhance the global perception.

Prof. Benedetti has worked on the placebo effect over many years and has given the placebo effect a rational and scientific background.

We are pleased that Prof. Benedetti has accepted our invitation and given a short summary of his important work.

– Wolfgang Grisold

Fabrizio Benedetti, MD, MAE

Fabrizio Benedetti, MD, MAE

Modern medicine and neurology have progressed in parallel with the advancement of biochemistry, anatomy, and physiology. By using the tools of modern medicine and neurology, today the physician and the neurologist can treat and prevent a number of diseases through pharmacology, genetics, and physical interventions, including surgery. In addition to this materia medica, the patient’s mind, cognitions and emotions play a central part as well in any therapeutic outcome. Placebo effects are at the very heart of these issues and, maybe paradoxically, they can be approached by using the same biochemical, cellular, and physiological tools of the materia medica, which represents an epochal transition from general concepts such as suggestibility and power of mind to a true physiology and biology.

Placebo effects remind us of the old tenet that patients must be both cured and cared for, and they teach us that these complex issues can today be investigated by using a physiological and neuroscientific approach. The intricate psychological factors involved can be approached through biochemistry, anatomy, and physiology, thus eliminating the old dichotomy between biology and psychology. This is both a biomedical and a philosophical enterprise that is changing the way we approach and interpret medicine, neurology, and human biology.

In the first case, curing the disease only is not sufficient, and care of the patient is of tantamount importance. In the second case, the philosophical debate about the mind-body interaction can find some important answers.

Although a terminological confusion still persists and the terms placebo effect and response are often used interchangeably, placebo effect could be considered different from placebo response. In the same way as the drug response is the global response to drug administration, so the placebo response is the whole response to placebo administration, including natural history of disease, regression to the mean, and such like.

Conversely, in the same way as the drug effect is the specific pharmacodynamic effect of a drug, so the placebo effect is the specific effect of placebo administration, that is, the real psychobiological phenomenon deriving from the psychosocial context around the patient. What neuroscientists have learned over the past few years is placebos are not inert substances. Instead, they are constituted of different words and therapeutic rituals as well as of different symbolic elements which, in turn, can influence the patient’s brain, thus they are amenable to classic neuroscientific investigation. Therefore, overall, a placebo is the whole ritual of the therapeutic act. Neuroscientists use the placebo effect as a model to understand how the human brain works, and indeed the study of the placebo effect is today a melting pot of concepts and ideas for neuroscience. In fact, there is not a single but many placebo effects, and there is not a single but many mechanisms across different conditions and interventions. The nocebo effect goes in the opposite direction, namely, clinical worsening after negative words that induce negative expectations.

In neurology, the most studied and understood conditions where placebo effects have been investigated in depth are pain and Parkinson’s disease. In pain, the opioid system activation by placebos is the most understood, as shown by the blockade of placebo analgesia by the opioid antagonist naloxone and by in vivo brain imaging of endogenous opioid release. By contrast, the cholecystokinin (CCK)-antagonist, proglumide, enhances placebo analgesia on the basis of the anti-opioid action of CCK, whereas the activation of the CCK type-2 receptors by means of the agonist pentagastrin disrupts placebo analgesia. Therefore, the activation of the CCK type-2 receptors has the same effect as the opioid receptor blockade, which suggests that the balance between CCKergic and opioidergic systems is crucial in placebo responsiveness in pain. Some brain regions in the cerebral cortex and the brainstem are affected by both a placebo and the opioid agonist remifentanil, thus indicating a related mechanism in placebo-induced and opioid-induced analgesia. A role of the CB1 cannabinoid receptors has also been found in some types of placebo analgesia that is not mediated by endogenous opioids. The CCK pro-nociceptive system has also been found to mediate the nocebo hyperalgesic effect. For example, expectation of pain increase leads to nocebo hyperalgesia, and this increase can be blocked by the CCK antagonist proglumide. Interestingly, there is compelling experimental evidence that the whole lipidic pathway, e.g. arachidonic acid, endogenous cannabinoid ligands, prostaglandins and thromboxane, is importantly involved in both placebo and nocebo effects, for example in hypoxia-induced headache.

In Parkinson’s disease, dopamine receptors are activated in both ventral (nucleus accumbens) and dorsal striatum when a placebo is administered. The release of dopamine corresponds to a change of 200% or more in extracellular dopamine concentration, and it is comparable to the response to amphetamine in subjects with an intact dopamine system. Intraoperative single-neuron recording in Parkinson patients during the implantation of electrodes for deep brain stimulation, shows that the firing rate of the neurons in the subthalamic nucleus and substantia nigra pars reticulata decreases after placebo administration, whereas the firing rate of thalamic neurons in the ventral anterior and anterior ventral lateral thalamus increases, along with the disappearance of bursting activity in the subthalamic nucleus. Importantly, from a clinical point of view, these neuronal changes are accompanied by a reduction in muscle rigidity.

It is clear from this brief description that placebos modulate the same biochemical pathways that are modulated by drugs, such as narcotics and non-steroid anti-inflammatory drugs for pain as well as dopaminergic agents for Parkinson’s disease, thus giving rise to the concept that placebos and drugs share common mechanisms of action. Overall, these findings provide compelling evidence for a true pharmacology and toxicology of words and of social interaction, thus leading to a new physiology of the doctor-patient relationship. Much remains to be done to understand where, when and how placebos work, that is, in which medical conditions, in which circumstances, and how they affect the brain across different neurological disorders. This challenge is certainly worth undertaking, as it will provide important pieces of information for clinical practice, clinical trials, and a better understanding of the human brain.•

Fabrizio Benedetti, MD, is professor of neurophysiology at the University of Turin Medical School, Turin, Italy, and professor of medicine, physiology, and neuroscience for the Innovative Clinical Training, Trials and Healthcare Initiative (ICTHI), Zermatt, Switzerland. He has been nominated member of The Academy of Europe and of the European Dana Alliance for the Brain. He is author of the book Placebo Effects (Oxford University Press, 3rd Edition, 2020), which received the Medical Book Award of the British Medical Association in 2009. In 2012, he received the Seymour Solomon Award of the American Headache Society, in 2015 the William S. Kroger Award of Behavioral Medicine from the American Society of Clinical Hypnosis, in 2023 the Lifetime Achievement Award by the Society for Interdisciplinary Placebo Studies.

For additional information:

  • Benedetti F, Carlino E, Piedimonte A (2016) Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol, 15: 736-747.
  • Benedetti F (2020) Placebo effects. Understanding the other side of medical care. 3rd Edition, Oxford: Oxford University Press.
  • Frisaldi E, Zamfira DA, Benedetti F (2021) The subthalamic nucleus and the placebo effect in Parkinson’s disease. In Swaab DF, Kreier F, Lucassen PJ, Salehi A, and Buijs RM (Eds). Handbook of Clinical Neurology: The Human Hypothalamus: Middle and Posterior Region. San Diego: Elsevier BV, pp 433-446.
  • Benedetti F, Frisaldi E, Shaibani A (2022) Thirty years of neuroscientific investigation of placebo and nocebo: the interesting, the good, and the bad. Annu Rev Pharmacol Toxicol, 62: 323-340.
  • Frisaldi E, Shaibani A, Benedetti F, Pagnini F (2023) Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review. Br Med J Open, 13: e077243.

WCN Update, Election Results, and WFN News

Welcome to World Neurology, the WFN newsletter, which contains several important contributions and has become the main instrument of information on WFN activities as well as other neurological activities worldwide.

I want to thank our editors, Steven Lewis and Walter Struhal, for their work for World Neurology, John England for JNS, and Walter Struhal for eNS. These publications help to promote neurology worldwide.

Council of Delegates (COD)

The electronic voting for the new positions was used by 65% of member societies. The results are:

  • Prof. M. Wasay was elected as a new trustee and will follow Prof. M. Freedman.
  • Prof. Richard Stark as the treasurer will be replaced by Prof. M. Freedman.

We thank Prof. Freedman for his activity as a trustee, and also thank both coopted trustees, Prof. Riadh Gouider and Prof. Marco Medina for their incredible input over the last two years, in particular to the needs of their regions. Prof. Stark will be in office until Dec. 31, 2023. From Jan. 1, 2024, Prof. Freedman will be in office as the new treasurer.

I also want to thank all individuals who applied for the positions but were not successful. Please keep supporting the WFN.

We welcome Chad as the 124th member of the WFN, as recommended by the membership committee.

In the COD meeting, the ongoing activities of officers, trustees, and committees were reported. Our global activities with the WHO and UN ECOSOC are developing well.

At the closing ceremony, the formal handover for the new congress site from Montreal to Seoul was finalized. We are happy to announce that Cape Town will be the WCN site in 2027.

Thanks to all other venues for their efforts to apply to be the site of the WCN.

WCN 2023 Montreal

The congress was co-hosted by the Canadian Neurological Society under Congress President Guy Rouleau. The WCN 2023 was a success in combining science, education, and the need for international cooperation and advocacy. In many sessions, the spirit of cooperation, education, advocacy, and global engagement was felt.

There were 2,300 in-person attendees and 1,300 online participants from 132 countries. There were also 2,297 submitted abstracts.

The scientific program was developed by the program committee and included 260 speakers from all regions of the world. The 10 plenary speakers discussed several topics, including the importance of cooperation with the WHO. The joint sessions with the WSO, MDS, and ILAE, as well as the joint sessions with the World Psychiatric Association and the World Federation of Neurosurgical Societies were introduced.

For the first time, the Young Neurologists were able to develop two sessions on their own. They also organized a patient day with a local committee and established a patient platform.

One highlight was the celebration of 10 years of WFN Training Centers in Africa and Mexico. Each training center received recognition. The chairs of the training centers reported on their important work.

In addition to the continuously successful and highly competitive and exciting Tournament of the Minds (won by Sri Lanka), several other congress initiatives were introduced, such as coffee talks, debates, meet the plenary lecturer, and interactive communications with social media.

Although the total number of attendees reached the goal, the low number of in-person attendees raises concern. The reasons will be subject to more analysis, including the attractiveness of the WCN concept, high costs of travel, visa issues, and decreasing industry support. As this was the first hybrid WCN, we are pleased with the participation from 132 countries.

It was also acknowledged that the WFN has its focus on global activities in advocacy and cooperation with the WHO and UN ECOSOC. Numerous meetings spread over the congress mirrored the spirit of cooperation and advocacy, and much effort was made to make the delegates and community aware of the WHO IGAP project.

The next WCN will be in Seoul Korea in 2025 jointly with the Korean Neurological Society. For 2027, Cape Town South Africa will be the congress site.

In 2024, the WFN will provide a virtual educational congress in the autumn called “WFN digital neurological Updates (WNU) 2024,” which will provide updates in the development of the most recent neurological conditions in association with teaching courses. The yearly COD in 2024 will be virtual and will provide a platform for informational meetings with the member societies in regard to international work, such as WHO and UN.

The trustees decided during the WCN to continue to provide WCN hybrid congresses and shorten the congress duration by one day to make the congress more compatible with the increasing time constraints.

The Specialty Group on Neuromuscular Diseases (ICNMD) will have an educational virtual meeting and a congress next year in Perth, Australia.

We are also glad on the series of educational days, jointly with the IHS/GPAC, the upcoming first joint educational AOAN WFN educational day on, and the AFAN WFN educational day on neuropathies and the ICNMD Digital.

We also shared the 14th EAN-AFAN Regional Teaching Course in Dar es Salaam, Tanzania, and were impressed by the program and the number of attendees, as well as the interactions between faculty and attendees.

Following the WCN congress, the WFN attended the 73rd regional WHO meeting in Astana, Kasakhstan, and also meetings with local high-ranking local officials were attended to promote the WHO IGAP locally.

We hope that this summary will give you an overview on the WFN activities, and we invite you to follow the website and social media. •

Click to see the sights from WCN 2023

 

We are pleased to announce a number of awards and recognitions

Named lectures:
See https://wfneurology.org/activities/soriano-award-lectures

Medal for Services to International Neurology | Awardee

Bhimsen Singhal (Bombay Hospital Institute, Mumbai, India)

Medal for Scientific Achievement in Neurology | Awardee

Avindra Nath (National Institutes of Health, Bethesda, Maryland)

Elsevier Awards

Best Research Paper

Long-Term Outcomes of Symptomatic Intracranial Atherosclerotic Stenosis Patients: A 3-Year Follow-Up
May Zin Myint

Best Research Paper

Topline Results of the Proof-Hd Pivotal Phase 3 Trial: Pridopidine’s Outcome on Function in Huntington Disease
Michael R. Hayden

Best Research Paper

Association Between Benzodiazepine and Alzheimer’s Disease Likely Driven by Prescription for Prodromal Phase Symptoms
Diego Legrand

Best Clinical Paper

Impact of Delirium Duration on Stroke Outcomes
Gabriel Suzart

Best Clinical Paper

Underemployment, Work Hour Reduction, and Income Loss: A Global, Multicentered, Cohort Study of Neuromyelitis Optica
Isabella Gomez Hjerthen

Best Clinical Paper

CADIIM Study: Cardiac and Autonomic Dysfunction in Idiopathic Inflammatory Myopathies
Samim Mondal

PRE-RECORDED:
Angela Vincent Award

Clinical and Radiological Spectrum and Outcomes in Patients of Subacute Sclerosing Panencephalitis
Jerry A. George

WFN-AAN: Ted Munsat Award

Prof. William Howlett, Tanzania

Angela Vincent Award:

Clinical And Radiological Spectrum and Outcomes in Patients of Subacute Sclerosing Panencephalitis
Jerry A. George, India

Winner of the Tournament of the Minds WCN Montreal 2023 

Sri Lanka (Thashi Chang, A.T. Alibhoy, Senaka Bandusena, and Manjula Caldera)

Improving Access to Medicines for Neurological Disorders

Report of the Sept. 5-6, 2023, meeting at the WHO Headquarters in Geneva, Switzerland.

By Ksenia Pochigaeva and Wolfgang Grisold

This two-day meeting in Geneva, Switzerland, was composed of worldwide high-level representatives looking at essential medicines for neurological disorders. It was organized through collaboration of several WHO departments, including the Brain Health Unit, the Medicines and Health Products Division and the Non-Communicable Diseases Department, as well as representatives of several WHO regional and country offices.

The WFN was represented at this meeting by its president, Wolfgang Grisold, with virtual participation of its trustees William Carroll and Alla Guekht. Dr. Carroll presented the results from the WFN Needs Registry Survey highlighting the importance of having treatments for neurological disorders on the list of essential medicines.

After opening statements, the meeting was initiated by a presentation from the Brain Health Unit of an ongoing landscape analysis, which examines data on various aspects of the existing treatment gap in neurological diseases and the factors that influence access to medicines. These were graphically presented as a “fishbone” diagram, which incorporated a wide array of components pertaining to prioritization of neurological conditions, selection, production, pricing, supply and monitoring of essential medicines. This highlighted the number of challenges, which need to be addressed both globally and at regional and country levels and served as a reference point for group discussion on specific actions for overcoming these challenges.

The WHO Essential Medicines List (EML) and Essential Medicines List for Children (EMLc) were discussed from several perspectives. These tools are of global importance, as all WHO member states (194) are recommended to have these drugs available. Although all of these medications are generics, they are still not accessible for patients in all countries. Reasons for this include disparities between the WHO model list and national EMLs, high cost of certain medicines, national policies regarding Universal Health Care (UHC), and reimbursement and the registration process not completed for all essential medicines in all countries.

This was outstandingly demonstrated in the report of a case study of 47 national EMLs from Africa, in which antiseizure and antiparkinsonism medicines from the WHO model list were used as tracer conditions for neurological disorders. This case study could be a model for other regions for a better understanding in what disparities need to be addressed to improve access to medicines for neurologic disorders.

Another issue that remains is related to the health workforce capacity, with many countries lacking a sufficient number of neurologists or physicians with training to diagnose and prescribe treatment for epilepsy and other neurological disorders.

The WHO EML is updated every two years through a thorough application and review process. The latest version of the list from 2023 includes cladribine, glatiramer acetate and rituximab for MS and levetiracetam among ASMs. Unfortunately, other neurological conditions, such as Parkinson’s disease, still lack medicines or optimized formulations on the EML.

The significance of this meeting was greatly supported by accounts from persons with lived experience, with Omotola Thomas speaking for people with Parkinson’s disease in Africa and Donna Walsh representing the IBE and speaking on behalf of people with epilepsy.

The WFN is grateful that the WHO is prioritizing medicine for the treatment of neurological disorders and will continue to be active in raising awareness on the WHO Model EML. •

Ksenia Pochigaeva is an intern with the WFN, and Wolfgang Grisold is WFN president.

Sights From WCN 2023, Montreal

WFN Reinforces Its Commitment to Advancing Global Neurology Education

Report of a press conference held at the World Congress of Neurology, Montreal, October 2023

On behalf of the WFN trustees, assisted by the WFN press support organization, Yakkety Yak.*

Key teaching initiatives bridge gaps in neurological care to promote brain health worldwide.

Neurological disorders are currently the second highest cause of death and the leading cause of disability worldwide. The new Global Burden of Disease (GBD) study shows that the number of people living with brain disease is expected to double by 2050.

One of the central challenges of addressing the growing burden of neurological diseases is the lack of available neurology care in under-resourced parts of the world. The World Federation of Neurology (WFN) is committed to finding new and innovative ways to educate and train an increasingly critical global neurology workforce to close this gap.

The World Health Organization (WHO) recommends one to five neurologists per every 100,000 people, but many low- and middle-income countries fall well below this number. In fact, the contrast in available neurologists between low-income and high-income countries is so stark that some of the lowest-income nations have 70 times fewer neurologists than countries like the U.S. and Canada.

“It’s impossible to develop appropriate care without education. It’s impossible to promote research without education,” said Dr. Alla Guekht, elected trustee of the World Federation of Neurology.

WFN will continue working with its regional neurological associations and member states to increase the availability of neurological care worldwide.

WFN Training Centers

WFN furthers its mission of fostering quality neurology and brain health worldwide by promoting global neurological education and training, with an emphasis on under-resourced parts of the world. WFN celebrates 10 years of WFN Training Centers, which facilitate training and knowledge exchange as well as visiting fellowships in global regions that have severe shortages of neurologists. WFN currently has training centers in Africa (Dakar, Senegal; Cairo, Egypt; Rabat, Morocco; and Cape Town, South Africa) and Mexico.

“The idea is not to go there and teach, but to empower regions to train their own neurologists,” said Dr. Wolfgang Grisold, president of the World Federation of Neurology. “This has been extremely productive, and while it does not fill the gap that is needed for neurologists in these and other regions, it does create important incentives.”

Future education efforts need to extend beyond neurology specialists to include training in neurological disorders and brain health at all levels of the health care system.

“Increasing the number of neurologists alone is not enough,” said Dr. Augustina Charway-Felli, president of the African Academy of Neurology. “We need to increase neurological awareness across health care providers of all levels — primary health care providers, general practitioners, specialists that are not neurologists and allied health care professionals.”

Global Partnerships and Visiting Neurologist Programs

WFN facilitates programs where residents or young neurologists visit hospitals in other countries for four to six weeks to gain exposure to different health systems and bring back their knowledge and experience to their home countries.

These initiatives are enabled by partnerships between the WFN and national neurological societies. They aim to enhance the exposure of young neurologists to their respective national neurological frameworks within a global context. This offers them the opportunity to connect with new peers and promote future collaborations among countries, universities, hospitals, and departments.

“We are very grateful for the many countries that receive either residents or young neurologists for short department visits,” said Dr. Grisold. “This has been very effective because people get exposed to a different health system for four to six weeks and come back with new ideas they can implement in their own departments and health care systems.”

Increasing Virtual Training

The COVID-19 pandemic required many health organizations to adapt to virtual modes of communication to expand access to training and education previously limited to in-person gatherings. WFN plans to continue utilizing virtual platforms to make critical neurology training and education available on a global scale.

“Increased virtual meetings empower us to be more relevant and efficient in all the different parts of the world,” said Dr. Guy Rouleau, president of the XXVI World Congress of Neurology. “Virtual education reduces costs for everyone —  both participants and the ones who generate the teaching — and we are also better able to tailor education and training to local needs.”

Ongoing education efforts must not only be more widely accessible to the global neurology community but also tailored to the specific needs of each country’s health systems and population.

WHO’s Intersectoral Global Action Plan (IGAP)

WHO’s Intersectoral Global Action Plan (IGAP) on epilepsy and other neurological disorders is a comprehensive framework aimed at reducing the global burden of neurological diseases and bolstering health care systems worldwide with the necessary resources and expertise. One of its goals is to increase training in neurological issues for the primary health care workforce and caregivers.

Dr. Tarun Dua, head of the World Health Organization’s Brain Health Unit, emphasized the need for a multifaceted approach to this complex issue beyond simply increasing the number of neurologists.

“The way we are building up our neurological workforce with the current education programs — even if we double the capacity, we are not going to bridge that gap in the nine years needed to meet the goals of the action plan,” said Dr. Dua. “We need to have a paradigm shift in our thinking.”

This paradigm shift must include not just new and expanded ways of training neurologists, but also reframing how we think of brain health as a human rights and global public health issue.

Spreading Education Through the World Congress of Neurology

The 26th World Congress of Neurology (WCN 2023) was held Oct. 15-19 in Montreal, Canada. WCN 2023 was the first in-person conference since the COVID-19 pandemic and brought together over 2,300 face-to-face and 1,300 virtual participants from 132 countries, including neurologists and advocates from the six global regions represented by our 124 WFN Member Societies. WFN also welcomed a new member society from the Republic of Chad.

“The resounding success of this year’s World Congress of Neurology is a testament to the unwavering dedication of the global neurology community,” said Dr. Grisold. “We’ve not only rejuvenated our connections but also extended our reach, embracing a new member society from the Republic of Chad. Together, we’ve paved the way for a brighter future in neurology.”

At WCN 2023, Dr. Steven L. Lewis, WFN secretary general and Congress committee chair, announced the locations for the next two biennial conferences:

  • 27th World Congress of Neurology, 2025, Seoul, South Korea
  • 28th World Congress of Neurology, 2027, Cape Town, South Africa

From 2024 onward, WFN will establish educational interim meetings called “WFN Digital Neurological Updates (WNU),” devoted to updates in neurology. These virtual meetings will be held in years between congresses and are intended to fill the gap between the bi-annual conferences.

“We will continue to find fresh ways to present the newest discoveries and the latest clinical information to attendees from around the globe,” said Dr. Lewis. “Our goal is to create the most accessible platform so that neurologists and other health care providers can bring this information back to their regions, to their hospitals and to their individual patients, to benefit from the latest developments in the field of neurology and to provide the best neurologic care to their patients wherever they may be.”

Looking toward 2024 and beyond, WFN is excited to find new and even more effective ways to support training for the global neurology community, foster regional exchange of knowledge and education, and prioritize brain health as a human right and a global public health issue. •

* This article was composed by our press consulting agency Yakkety Yak, Inc., on behalf of the WFN. It is based on interviews and communications and contains no industry influence or bias.

From the Editors

We’d like to welcome all readers to the December issue of World Neurology, the last issue of 2023.

The issue begins with the President’s Column, where WFN President Dr. Grisold provides an overview and recap of the many activities of the World Congress of Neurology (WCN), which recently occurred in Montreal, including the Council of Delegates meeting. Dr. Grisold also updates us on other ongoing initiatives and global activities of the WFN. In an accompanying article, the many WFN activities that were highlighted at the WCN press conference are summarized. Later in the issue, a photo montage from the WCN shows a sampling of the activities from this remarkable and highly attended event.

Three articles in this issue discuss essential medicines for neurological disorders (issues that the WFN is highly involved in), including a global overview of this important issue by Drs P. Brhlikova, R. Walker, N. Fothergill–Misbah, and AM Pollock, a report by Dr. Grisold and Dr. Pochigaeva on the World Health Organization (WHO) meeting on improving access to neurological medicines, and an update on the recently approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) on the WHO essential medicines list, by Drs. B. Yamout, T. Kalincik, J. Laurson-Doube, B. Hemmer, and S. Viswanatha.

In another article, Dr. Prince Kazadi, Director of Aslek Epilepsy in the Democratic Republic of Congo (DRC) along with his collaborators, Drs. M. Lubendo, D. Tshiyuk, and N. Kimponto, discuss the activities of their organization with regard to research, staff training, community education, and patient care for patients with epilepsy.

In this month’s history column, Dr. Peter J. Koehler describes the history and theories of speculations about the relation between the function of the brain and its movements. In a second historically based article in the issue, Drs. Domenico Inzitari and Vladimir Hachinski provide their analysis of the possible role of Tourette’s syndrome in a famous figure in Spanish history.

Several regional meetings are also reported in this issue, including the report by Dr. Alex Razumovsky from the WFN’s Neurosonology Specialty Group and his colleagues Dr. K. Potapova, L. Sokolova, D. Andreichenko, and S. Dudukina, who report on workshops in Ukraine that discussed clinical use of transcranial Doppler ultrasonography for patients with various disorders, including its application for wartime traumatic brain injury. Drs. Amir Molaie and David Liebeskind report on the 2023 International Symposium on Thrombolysis/Thrombectomy and Acute Stroke Therapy and the Symposium on Collaterals on the Brain that occurred at the University of California, Los Angeles, and was attended by global experts.

Drs. Satish Khadilkar and Gagandeep Singh announce the recent publication of the second edition of the Indian Academy of Neurology (IAN) Textbook of Neurology, a highly comprehensive and up-to-date two-volume textbook relevant to neurologists worldwide.

Finally, this issue features a heartfelt obituary for Prof. Hany Aref, a remarkable neurologic leader and a wonderful man. Although he is so greatly missed by those many of us who were fortunate enough to know him and to learn from him, his legacy as a leader in neurology and in stroke care in Egypt and worldwide will be long-lasting.

In closing, in this last issue of 2023, we want to wish everyone a wonderful new year and look forward to sharing additional information with you about the WFN and neurology and neurologists around the world in our future issues of World Neurology. •

IAN Textbook of Neurology

The book encompasses both the theoretical and practical aspects of neurology.

by Satish V. Khadilkar and Gagandeep Singh

The “IAN Textbook of Neurology,” edited by Satish V. Khadilkar and Gagandeep Singh, is a comprehensive two-volume sourcebook for students and postgraduates in neurology and practicing neurologists. The book has been compiled by an experienced team of authors from various parts of India and international contributors. The book is well structured into various sections, including history and examination methods, neuroanatomy and neurophysiology, the clinical and diagnostic approaches to various nervous system diseases, and therapeutic aspects.

This book is unique in terms of encompassing both the theoretical and practical aspects of neurology. The detailed description of neurological examination methods along with applied aspects of it will be extremely useful to students. The inclusion of case examples in appropriate places makes it an interesting read. The online version also provides students with multiple-choice questions for self-assessment and illustrative case videos for better understanding.

The second edition adds one more distinctive feature of providing a regional context in various neurological disorders where such peculiarities exist. This is a thoughtful attempt to provide insights into unique demographics, epidemiology, and disease behaviors. This should also motivate the researchers in the country. This area should be worked upon further in the next edition to combine the global and Indian perspectives. The data from a country with such a large population will add value to the world literature. In recent times, the fields of neurogenetics and immunology have been rapidly evolving. Although this book provides primers of both these fields, the coming editions will certainly see more incorporation of these sciences and their impact on the neurology practice.

The book features a foreword by
Dr. Wolfgang Grisold, president of the World Federation of Neurology, and is available on various platforms globally. •

History and the Tourette Syndrome: The Case of Conde Duque de Olivares

The neuropsychiatric syndrome that may have affected the Conde Duque de Olivares, who in the early seventeenth century had almost absolute power in deciding internal or foreign affairs of the Spanish Kingdom.

Gaspar de Guzman, Count-Duke Olivares *oil on canvas *67 x 54,5 cm *circa 1638

BY DOMENICO INZITARI, MD, AND VLADIMIR HACHINSKI, MD, DSC

Early in the seventeenth century, France and Spain vied for predominance, led by Cardinal Richelieu (Armand Jean du Plessis de Richelieu,1585-1642) and the Conde Duque de Olivares (Gaspar de Guzmán y Pimentel, 1587-1645) respectively. Gregorio Marañon y Posadillo (1887-1960), founder of Spanish endocrinology, documented in a now classic biography manic depressive swings in the mood of Olivares. Temper and behavior disorders were also reported by other contemporary or modern biographists. We decoded, translated, and examined a secret report of a Medici family’s (Grand Dukes of Tuscany, Italy, at that time) representative in the Spanish Court, extant as original manuscript in the State Archives of the city of Florence, Italy. There, it affirmed that he had an unhealthy mind, and reported about continuous and large movements affecting his body.

We suggest that the likeliest explanation of these abnormal movements in someone with episodic mood swings is Tourette Syndrome, a recognized association.

Ancient and modern history provide examples of individuals capable of changing the destinies of the world, particularly if they gained absolute power in ruling a nation. When a ruler becomes an “Enlightened Prince,” outlined by Machiavelli (Niccolò di Bernardo dei Machiavelli, 1469-1512) it can be a favorable situation. However, when a ruler’s political decisions are influenced by an abnormal personality or a definite neurological disorder, the results might be disastrous.

In this article, we discuss the neuropsychiatric syndrome that may have affected the Conde Duque de Olivares, who in the early seventeenth century had almost absolute power in deciding internal or foreign affairs of the Spanish Kingdom, and was possibly affected by the Tourette Syndrome. The presence of personality traits linked with this neurological disorder may have had a role in Spain’s struggle with France for the domination of Europe.

In addition to the Monanni’s Dispatch, we drew the information for describing the syndrome presented by Olivares from two modern Olivares’ biographies, the one of Dr. Gregorio Marañon1, a Spanish endocrinologist, and the other of the eminent historian John Huxtable Elliot (1930-2022)2. Another source was a book, in which the same Elliot compared Cardinal Richelieu with Olivares3.

Historical Background

In 1621, King Philip III of Spain died, and Philip IV, a boy of 16 left the effective power of kingship in the hands of his former gentleman of the chamber, the Conde Duque de Olivares. Court favorite and prime minister since 1623, Olivares governed Spain with almost absolute authority for nearly 20 years. He embarked on a policy of uniting what he considered Spain’s anachronistic division of kingdoms, which ultimately led to revolts in the 1640s. He involved Spain in the Thirty Years’ War to establish Spanish-Austrian Habsburg domination of Europe.5 This plan was in opposition to those of the French plenipotentiary during the reign of Louis XIII, Cardinal Richelieu, who was also strongly determined to reaffirm the role of France as a great international power. The struggle was conducted by these two men on both diplomatic and military grounds. After alternating vicissitudes, it ended with the success of France and Cardinal Richelieu, and the defeat of Spain and Olivares.

The Disorders of Mood

Monanni4 reported about Olivares: “It is said he has an unhealthy mind, as since he was young, he had clear episodes of insanity, for which he had to be cured.”

Marañon1 described Olivares as the typical cyclothymic personality. Elliot3 confirms Marañon observations: “Moments of euphoria were succeeded by dark periods of discouragement, and both moods may indeed have run to the extremes.” Adverse events such as political failures or attacks by his opponents made him feel defeated and depressed. However, once these feelings abated, he found courage, vigor, and willingness to plan new enterprises and machinations (Contarini, quoted by Marañon).

Depressive phases were characterized by frustration, feelings of sin, fugues. On the other hand, he displayed an inclination for grandiose designs; especially in the first years of power, there was a phase of continuous hypomanic excitement.1

The Movement Disorder

Despite the detailed description of the physical and psychopathological traits of Olivares, Marañon’s biography did not mention any motor abnormalities. In contrast, Monanni’s Dispatch4 includes a brief description of involuntary movements “continuous and large, affecting his body, that is, his hands, head, and legs, while dealing with the most important affairs with his ministers.”

The Temper and Behavioral Disorders

In a background of long-lasting mood oscillations, character instability, and irritability are also reported: Monanni4 describes his character as often mutable, “so that it is impossible to be in sympathy with him.” Based on other contemporary accounts, Elliot writes2,3 that “Olivares suffered from acute hypersensitivity … was prone to sudden, terrifying bursts of temper … he lost his temper with people, with events, with fortune, with himself … he indulged in long tirades, and banged the table in outbursts of fury, although he could be affable, smooth, and indeed ingratiating in private conversations.” According to Marañon1, Olivares inherited from his father the irascible character, excessive meticulousness, and prolixity in details, traits that are typical of an obsessive personality. Marañon also notes that character abnormalities were reported in several other members of the family.

Interpretation of the Neuropsychiatric Syndrome

The available description of abnormal movements is too short for any definition based exclusively on the features of the motor disorder. So, the clinical interpretation can be made considering the whole neuropsychiatric picture. Movements were large and continuous, and supposedly activated by emotional stress (“when dealing with the most important affairs with his ministers”). The possible diagnoses include chorea, torsion dystonia, tics, and other complex involuntary movements that are commonly considered distinct from tics such as stereotypes, hyperekplexia, akathitic movements, and that can occur in the restless legs syndrome.6

Huntington’s disease should be excluded, owing to the absence of any ancestor affected, and of mental deterioration till the late years of Olivares’ life, although death occurred when he was only 58. Hereditary nonprogressive chorea of early onset, although rare, should also be considered. Another possibility is torsion dystonia: We can only postulate that torsion dystonia with the continual hyperkinesia usually twisting in pattern, and the sustained abnormal postures should have been so functionally disabling, to be not easily missed by the Olivares’ biographists.

We suggest that the association of involuntary movements with the typical personality and character traits is the strongest support of the hypothesis of Tourette Syndrome.

Compared with the general population, individuals with Tourette Syndrome appear to have an increased frequency of many different behavioral symptoms, including impulsivity and emotional lability6, anger, and short temper.7 Obsessional compulsive symptoms in particular have received close attention6. It has long been established that there are links between obsessive-compulsive disorder and depressive illness. Depression and anxiety scores are higher among Tourette Syndrome patients compared to normal controls.8 Among patients with Tourette Syndrome, Comings & Comings7 have found an increased prevalence of phobias and panic attacks, obsessions and compulsions, depression, and mania. These authors conclude that all of these psychopathological abnormalities may be linked to a common genetic disorder causing disinhibition of the limbic system.

Conclusions

Although the role of Olivares in relation to the decline of Spain in the seventeenth century is controversial, many clues from contemporary observers and modern historians suggest that his psychological traits undoubtedly influenced his political decisions.

The presence of involuntary movements associated with psychopathologic features commonly observed in Tourette Syndrome make this diagnosis plausible.

Acknowledgments

We thank Dr. Francesco De Feo, Egle Casale Inzitari and Marco Inzitari for their assistance in decoding and translating the Monanni’s Dispatch. •

Domenico Inzitari is with the Italian National Research Council, Neuroscience Institute, Sesto Fiorentino, Florence, Italy. Vladimir Hachinski is with the Department of Clinical Neurological Sciences, Robarts Research Institute, University of Western Ontario, London, Canada, and is a past president of the WFN.

This article represents the opinions and interpretations of the authors and does not necessarily reflect the opinion of the WFN.

References

1. Marañon G. El Conde-Duque de Olivares. 3rd Edition, Madrid, 1952.

2. Elliot JH. The Count Duke of Olivares. Yale University Press, New Haven and London, 2nd Printing, 1988.

3. Elliot JH. Richielieu and Olivares. Cambridge University Press, Cambridge, 3rd Printing, 1987.

4. Monanni B. Monanni’s Dispatch. Mediceo, filza 4963, 14 Nov 1637, State Archives, Florence.

5. The New Encyclopaedia Britannica. Olivares Conde-Duque de. Micropaedia 1984; vol. VII, p.520.

6. The Tourette Syndrome Classification Study Group. Definition and Classification of Tic Disorders. Arch Neurol 1993; 50: 1013-1016.

7. Comings D, Comings B. A controlled study of Tourette Syndrome I-VII. Am J Hum Gen 1987; 41: 701-866.

8. Robertson MM, Shelley C, Baker J, Flynn D. The psychopathology of Gilles de la Tourette’s Syndrome. A Controlled study. Br J Psychiatry 1993; 162: 114-117.

Prof. Hany Mohammed Aref (1961-2023)

Prof. Hany Mohammed Aref

By Riadh Guider and Maged Abdel Naseer

The medical and neurology communities are deeply saddened by the passing of Prof. Hany Aref, on July 26, 2023, at the age of 62 years. He made an indelible impact on neurology and stroke at the national, regional, and international levels.

He was deeply committed to serving neurology in Egypt as head of the neurology department at Ain Shams University in Cairo. He focused on brain health care, clinical education, and research to improve the treatment for patients with neurological diseases. Prof. Aref was the general secretary of the Egyptian Society of Neurology, Psychiatry, and Neurosurgery.

He was the founder of the recently inaugurated stroke unit at Ain Shams University on Sept. 5, 2023. This Center of Excellence for Comprehensive Stroke Services was Prof. Aref’s life dream. It took four years to build, and he raised 100 million Egyptian pounds for its construction. A mammoth and lasting achievement.

His commitment and efforts extended regionally through his significant role in Arab organizations. He was the treasurer of Pan Arab Union of Neurological Societies (PAUNS). He was also a member of the scientific committee of Middle East North Africa Committee for Research and Treatment in Multiple Sclerosis (MENACTRIMS).

Internationally, he served as WFN delegate of the Egyptian Society of Neurology, Psychiatry & Neurosurgery, and lately was a member of the WFN Nominating Committee.

Dedicated stroke bed at the stroke unit at Ain Shams University.

He was an exceptionally valued member of other international neurological organizations; a Fellow of American Academy of Neurology (FAAN), member of European Academy of Neurology, and member of editorial board of the European Journal of Neurology.

In the stroke field, he served as vice president of the Middle East and North Africa Stroke Organization (MENASO). He significantly contributed to the World Stroke Organization (WSO) as a member of the Future Leader Taskforce. He was also a fellow of the European Stroke Organization (FESO).

Although it is tragic to think of Prof. Aref passing so early, he left behind a lifetime of extraordinary memories. He was a great teacher and mentor to many young neurologists and researchers. 

He was a kind person and a great colleague. It was a great pleasure and honor to work alongside him.

Our deepest and heartfelt condolences to his wife Prof. Nevine Al Nahas, his two sons, friends, and colleagues. The global neurological community will fondly remember him. •

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