Valproate and folate: Congenital and developmental risks.

Increasing awareness of the congenital and developmental risks associated with the use of sodium valproate (VPA) has led to recent European guidelines designed to avoid the use of this drug in pregnancy if effective alternative treatments are available. In the general population, it is well established that periconceptual folic acid reduces the risk of neural tube defects (NTDs) and possibly other congenital abnormalities. We here review the evidence 1) that VPA interferes with one-carbon metabolism, including the transport of methylfolate into the brain and the placenta by targeting folate receptors; 2) that VPA effects on the folate metabolic system contribute to congenital and developmental problems associated with VPA exposure; and 3) that genetic factors, notably polymorphisms related to one-carbon metabolism, contribute to the vulnerability to these VPA-induced risks. Based on these facts, we propose that the standard periconceptual use of 400 µg of folic acid may not adequately protect against VPA or other antiepileptic drug (AED)-induced congenital or developmental risks. Pending definitive studies to determine appropriate dose, we recommend up to 5 mg of folic acid periconceptually in at-risk women with the caveat that the addition of supplementary vitamin B12 may also be prudent because vitamin B12 deficiency is common in pregnancy in some countries and is an additional risk factor for developmental abnormalities.

The earliest experimental convulsions by Joseph Priestley in 1766 friendship with Benjamin Franklin.

In 1766, Joseph Priestley (1733-1804) was the first to systematically demonstrate the universal convulsive effect of an electrical discharge applied to the head of all the several species studied. We here republish his overlooked experiments, which often resulted in death, and which ante date the scientific studies of the electrical functions of the brain, the role of "discharges" in seizures, and experimental epilepsy by about a century. Priestley's studies of electricity were influenced by those of Benjamin Franklin (1706-1790), who became a good friend during Franklin's prolonged period in London between 1757 and 1775. Both were elected Fellows of the Royal Society and both were awarded the Copley Medal of that Society. Priestley's experiments are relevant to the history of epilepsy and neuropsychiatry, and to the modern study of sudden unexplained death in epilepsy (SUDEP).

Neurology and psychiatry in Babylon.

We here review Babylonian descriptions of neurological and psychiatric disorders, including epilepsy, stroke, psychoses, obsessive compulsive disorder, phobias, psychopathic behaviour, depression and anxiety. Most of these accounts date from the first Babylonian dynasty of the first half of the second millennium BC, within a millennium and a half of the origin of writing. The Babylonians were remarkably acute and objective observers of medical disorders and human behaviour. Their detailed descriptions are surprisingly similar to modern 19th and 20th century AD textbook accounts, with the exception of subjective thoughts and feelings which are more modern fields of enquiry. They had no knowledge of brain or psychological function. Some neuropsychiatric disorders, e.g. stroke or facial palsy, had a physical basis requiring the attention of a physician or asû, using a plant and mineral based pharmacology; some disorders such as epilepsy, psychoses, depression and anxiety were regarded as supernatural due to evil demons or spirits, or the anger of personal gods, and thus required the intervention of the priest or asipu; other disorders such as obsessive compulsive disorder and psychopathic behaviour were regarded as a mystery. The Babylonians were the first to describe the clinical foundations of neurology and psychiatry. We discuss these accounts in relation to subsequent and more modern clinical descriptions.

The origins and early development of the ILAE/IBE/WHO global campaign against epilepsy: Out of the shadows.

The International League Against Epilepsy (ILAE)/International Bureau for Epilepsy (IBE)/World Health Organization (WHO) Global Campaign Against Epilepsy was launched in Geneva and Dublin in the summer of 1997. The second phase of the Campaign was launched by a major event in Geneva, led by WHO Director General Dr. Gro Harlem Brundtland in February 2001. Since then, the Campaign has been gathering momentum around the world culminating in the WHO General Assembly Resolution (WHA 68.20) on Epilepsy in May 2015 supported by 194 countries. Recently, the World Federation of Neurology and other neurological non-governmental organizations (NGOs) have joined forces with the Epilepsy Campaign, leading to the WHO General Assembly Resolution (WHA 73.10) in May 2022 promoting a 10-year Intersectoral Global Action Plan (IGAP) for Epilepsy and Other Neurological Disorders. I was privileged to serve as the first Chairperson of the Global Campaign Against Epilepsy and this year all my documents and correspondence relating to the Campaign have been delivered to the Wellcome Collection in London. These are the basis for this detailed account of the origins and early development of the Campaign. I describe the events leading to the birth of the concept, planning for the Campaign, the launch, development, and the achievements of phase one. This first phase focused on awareness raising, education, and involvement, especially within WHO, ILAE, and IBE, including a series of five Regional Public Health meetings and Declarations on Epilepsy. In 1999, the WHO raised the status of the Campaign to the highest level, the first ever for a Non-Communicable Disease, resulting in the high profile launch of phase two in 2001, paving the way to the continuing global momentum and achievements, including the 2015 and 2022 WHO Resolutions.

Charcot's international visitors and pupils from Europe, the United States, and Russia.

The foundation by Jean-Martin Charcot (1825-1893) of the Salpêtrière School in Paris had an influential role in the development of neurology during the late-nineteenth century. The international aura of Charcot attracted neurologists from all parts of the world. We here present the most representative European, American, and Russian young physicians who learned from Charcot during their tutoring or visit in Paris or Charcot's travels outside France. These include neurologists from Great Britain and Ireland, the United States, Germany and Austria, Switzerland, Russia, Italy, Spain, Belgium and the Netherlands, Scandinavia and Finland, Poland, Bohemia, Hungary, and Romania. Particularly emblematic among the renowned foreign scientists who met and/or learned from Charcot were Charles-Edouard Brown-Séquard, who had interactions with Paris University and contributed to the early development of British and American neurological schools; John Hughlings Jackson, who was admired by Charcot and influenced French neurology similarly as Charcot did on British neurology; Silas Weir Mitchell, the pioneer in American neurology; Sigmund Freud, who was trained by Charcot to study patients with hysteria and then, back in Vienna, founded a new discipline called psychoanalysis; Aleksej Yakovlevich Kozhevnikov and almost all the founders of the Russian institutes of neurology who were instructed in Paris; and Georges Marinesco, who established the Romanian school of neurology and did major contributions thanks to his valuable relation with Charcot and French neurology.

Obsessive compulsive disorder and psychopathic behaviour in Babylon.

BACKGROUND: The history of obsessive compulsive, phobic and psychopathic behaviour can be traced to the 17th century AD. METHODS AND RESULTS: We draw attention to these behaviours in a Babylonian cuneiform medical text known as Shurpu. These three categories were united in the Babylonian mind around the concept of the mamit 'oath' idea, the behaviour habits being so unbreakable it appeared that the subject had sworn an oath to do or not to do the action involved. The behavioural accounts were entirely objective, including what we would call immature, antisocial and criminal behaviour, and obsessional categories of contamination, aggression, orderliness of objects, sex and religion. They do not include subjective descriptions of obsessional thoughts, ruminations or the subject's attitude to their own behaviour, which are more modern fields of enquiry. CONCLUSIONS: The Babylonians had no understanding of brain or psychological function but they were remarkable describers of medical disease and behaviour. Although they had both physical and supernatural theories of many medical disorders and behaviours, they had an open mind on these particular behaviours which they regarded as a 'mystery' yet to be 'resolved'. We are not aware of comparable accounts of these behaviours in ancient Egyptian or classical medicine. These Babylonian descriptions extend the history of these disorders to the first half of the second millennium BC.

Hysteria, conversion and functional disorders: a neurological contribution to classification issues.

Proposals by psychiatrists to reclassify conversion disorder in DSM-5 and ICD-11 are proving difficult and controversial. Patients with conversion disorder usually present initially to neurologists, who often use different concepts and terminology. History and clinical practice suggest that the way forward is to seek agreed principles and a common understanding between the two disciplines, preferably in a single universal classification.

Improvement Initiative to Develop and Implement a Tool for Detecting Drug-Drug Interactions During Oncology Clinical Trial Enrollment Eligibility Screening.

OBJECTIVES: Screening subjects for drug-drug interactions (DDIs) before enrollment in oncology clinical trials is integral to ensuring safety, but standard procedures or tools are not readily available to screen DDI in this setting. Our objectives were to develop a DDI screening tool for use during oncology clinical trial enrollment and to test usability in single-center and multicenter pilot studies. METHODS: A multistage approach was used for this quality improvement intervention. Semistructured interviews with individuals responsible for DDI screening were conducted to develop a prototype tool. The tool was used for screening DDI in subjects enrolling in National Clinical Trials Network trials of commercially available agents during a single-center 3-month pilot. Improvements were made, and a 3-month multicenter pilot was conducted at volunteer SWOG Cancer Research Network sites. Participants were surveyed to determine tool usability and efficiency. RESULTS: A tool was developed from semistructured interviews. A critical feature was reporting which medications had specific pharmacokinetic and pharmacodynamic characteristics including transporter and cytochrome P450 substrates, inhibitors, or inducers and QT prolongation. In the 12-site study, average (SD) DDI screening time for each patient decreased by 15.7 (10.2) minutes (range, 3-35 minutes; P < 0.001). Users reported the tool highly usable, with >90% agreeing with all positive usability characterizations and disagreeing with all negative complexity characterizations. CONCLUSIONS: A DDI screening tool for oncology clinical trial enrollment was created and its usability confirmed. Further testing with more diverse investigator sites and study drugs during eligibility screening is warranted to improve safety and data accuracy within clinical trials.

Epilepsy and Neuroscience: Evolution and Interaction.

Neuroscience is a relatively new and fashionable word that emerged in the 1950s in several countries, including the UK, to describe a multidisciplinary clinical and laboratory approach to the study of the brain, mind, and neuropsychiatric disorders. However collaborative study of neurological and psychiatric disorders can be traced to the 17th century with roots in antiquity. I describe the evolution of our understanding of epilepsy beginning with the first detailed clinical descriptions, associated with supernatural theories, in Babylonian medicine in the second millennium BC. Interest in natural causation arose in the Greco-Roman period when it was first suggested that "the sacred disease" was a disorder of the brain. However, this theory did not take root until the 17th and 18th centuries AD when epilepsy began to be separated from other "convulsive" diseases, including hysteria. In the 19th century developments in neuropathology and our understanding of cortical localization led to the much-debated separation of idiopathic from symptomatic epilepsy which continues to influence international classifications of seizures and epilepsies. Also in the 19th century, the concept of seizures as electrical discharges in the brain evolved, reinforced in the 20th century by the discovery of the electroencephalogram. For many reasons, people with epilepsy have experienced a high incidence of cognitive and psychosocial disorders. Epilepsy, which is a global problem, has, therefore, remained a bridge between neurology and psychiatry. Furthermore, the study of epilepsy continues to shed light on brain function and other neuropsychiatric disorders.

The clinical concept of epilepsy.

This article reviews the history of clinical concepts of epilepsy and its classification, especially in the last 100 years. Throughout its recorded history of 3 to 4 millennia, epilepsy has always been defined by its most dramatic symptoms, for example, falling, motor activity or loss of consciousness, but separation from other causes of the same paroxysmal symptoms has always proved challenging. For over a century there has been some semantic confusion whether to call the various paroxysms fits, convulsions, seizures, or epilepsies. Since the middle of the 19th century a great unresolved debate has continued about whether recurrent seizures or epilepsy should be viewed as a separable symptom of underlying brain disease or as one or more idiopathic diseases or syndromes, with an inherent age-related natural history; or indeed viewed as both a symptom and a disease. A major advance in the 20th century is that vascular theories of epilepsy, which reached their peak with Turner in 1907, have been replaced by electromagnetic discharges, based especially on the work of Todd, Jackson, Berger, Lennox, and the Gibbs, culminating eventually in new ILAE classifications of seizures (1981) and epilepsy syndromes (1989). However 21st century uncertainties about symptomatic versus idiopathic or cross-sectional (seizures) versus longitudinal (epilepsy) approaches to the problem very much reflect similar divergences of view a century ago. More attention is now being directed at interseizure events and processes which may lead either to remission or intractability with associated cognitive and psychosocial consequences. The search for the elusive essence, diathesis or predisposition to epilepsy, including seizure threshold, continues.

Epilepsy, psychiatry, and neurology.

This article reviews the relationship between the psychiatry and neurology of epilepsy, especially in the last 100 years. Throughout most of its recorded history of 3 to 4 millennia epilepsy has been viewed as a supernatural or mental disorder. Although first suggested by Hippocrates in the 5th century B.C., the concept of epilepsy as a brain disorder only began to take root in the 17th and 18th centuries. The discipline of neurology emerged from "nervous disorders" or neuropsychiatry in the late 19th century, when vascular theories of epilepsy predominated. By the turn of the 19th century psychiatry and neurology were diverging and epilepsy remained to some extent in both disciplines. It was only in the middle of the 20th century with the development of electromagnetic theories of epilepsy that the concept of epilepsy per se as a neurological disorder was finally adopted in international classifications of disease. This was associated with a refined definition of the ictal, pre-, post-, and interictal psychological disorders of epilepsy, which have contributed to a renaissance of neuropsychiatry. At the beginning of the 21st century and the centenary of the ILAE psychiatry and neurology have been converging again, led in some respects by epilepsy, which has provided several useful models of mental illness and a bridge between the two disciplines.