Edward H. Reynolds

Homocysteine, folate, methylation, and monoamine metabolism in depression

OBJECTIVES Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.

ILAE/IBE/WHO Global Campaign "Out of the Shadows" : Global and Regional Developments

The spring of 2001 has seen two major events in the International League Against Epilepsy (ILAE)/ International Bureau for Epilepsy (IBE)/World Health Organization (WHO) Global Campaign to bring epilepsy “out of the shadows.” On February 12, the second-phase launch of the Campaign took place at WHO headquarters, Geneva, led by the Director General, Dr. Gro Harlem Brundtland, with the participation of senior WHO staff from the “clusters” and departments responsible for or related to the Campaign, the Regional Mental Health officers from all six WHO Regional offices, John Bowis, MEP, representing national governments and the European Parliament, the Executive Committees of ILAE and IBE, the Executive Board of the Campaign, many representatives from national Chapters of the League and the Bureau, and invited guests including several national ambassadors to WHO (1) (Figure 1). On March 22, the European “White Paper” on Epilepsy was launched at the European Parliament by John Bowis in the presence of politicians, professionals, patients, and public from all over Europe, the event being generously sponsored by the pharmaceutical firm, UCB (2). These global and regional events are the latest milestones in the ILAE/IBE/WHO Global Campaign to bring Epilepsy “out of the shadows,” which was launched in 1997 (3). They also mark a new phase, intensification, and status of the Campaign, which is designed ultimately to assist national governments and epilepsy organisations to develop their own “out of the shadows” plans and initiatives.

Psychoses of epilepsy in Babylon: The oldest account of the disorder

We have previously published translations of Babylonian texts on epilepsy and stroke, which we believe to be the oldest detailed accounts of these neurological disorders from the second millennium BC. We now present a short Babylonian text, which clearly describes what are today known as interictal or schizophrenia‐like psychoses of epilepsy. The text includes many of the classical symptoms of the syndrome, for example, paranoid delusions, hallucinations and mood disorders, as well as religiosity and hyposexuality, which have only been crystallized in the twentieth century. The Babylonians were remarkably good observers of human disease and behavior but had little or no understanding of pathology or brain function. Although they recognized many natural causes of disease, epilepsy and behavior disorders were attributed to supernatural, usually evil forces, the forerunner of the Greek concept of the Sacred Disease.

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.

Todd, Hughlings Jackson, and the electrical basis of epilepsy

John Hughlings Jackson is widely credited with the first electrical theory of epilepsy (1873), which was confirmed by the experimental studies of Hitzig and Ferrier. His views are summarised in his famous Lumleian lectures to the Royal College of Physicians in 1890. Robert Bentley Todd, however, had earlier developed an electrical theory of epilepsy, which he presented in his own brilliant Lumleian lectures to the Royal College of Physicians in 1849. Todd was influenced by the electrical discoveries of his contemporary, Michael Faraday, and thought of the brain as having battery like properties that led to the sudden discharge of electrical energy (nervous force) in epilepsy. Unlike Hughlings Jackson, Todd was an anatomist and physiologist as well as a physician, and he did his own electrical experiments in rabbits to prove his theory, something Hughlings Jackson, who relied on Ferrier for scientific and experimental support, could never have done. There is no mention of Todds Lumleian lectures in Hughlings Jacksons later lectures and writings, nor in those of Hitzig or Ferrier. Todds remarkable observations and lectures, and his electrical theory of epilepsy deserve to be drawn to the attention of the medical and scientific community.

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.

Todd, Faraday, and the electrical basis of epilepsy

Summary:  Purpose: To consider the origins of our understanding of the electrical basis of epilepsy in the light of the Lumleian lectures to the Royal College of Physicians in London for 1849, “On the pathology and treatment of convulsive diseases,” by Robert Bentley Todd (1809–1860).

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.

Jackson, Todd, and the Concept of “Discharge” in Epilepsy

Summary:  Purpose: To explore the historical origins of the modern concept of electrical discharges in the brain in epilepsy.

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 ašipu; 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.