Azañón's disease. A 19th century epidemic of neurolathyrism in Spain.

The cultivation and consumption of grasspea (Lathyrus sativus) in Spain probably dates back centuries, especially during times of famine when the neurotoxic potential of this legume was expressed in the form of a spastic paraparesis known as neurolathyrism. Little known outside the country, the epidemic of neurolathyrism in the years following the Spanish Civil War (1936-1939) came to affect more than a thousand people. In late 1872, during the Six Years Revolutionary Term, young Alejandro San Martín Satrústegui (1847-1908), then editor of the popular weekly El Siglo Médico, travelled to Azañón, a remote village in the province of Guadalajara, to clarify a so-far unknown disease. We analysed the original article published in 1873 by San Martin, as well as communications sent by El Siglo Médico readers reporting similar cases in many other Castilian provinces. San Martín's neurological findings in seven personally examined cases were astonishingly accurate; he concluded the subjects' neurological deficits resulted from injury to the lateral columns in the lower portion of the spinal cord. Description of the clinical findings provided both by San Martín, and by the readers of El Siglo Médico, leave no doubt as to the diagnosis of neurolathyrism. However, none suspected the patient's staple food was the determinant cause of the disease. San Martín proposed the eponym Azañón's disease for lack of a better name the same year (1873) in which Cantani in Italy introduced the term lathyrism. The epidemic of neurolathyrism that affected many Castilian towns represents one of the best-documented in Europe during the last third of the 19th century.

Neurotoxic Weapons and Syndromes.

The modern era of chemical and biological warfare began in World War I with the large-scale production and use of blistering and choking agents (chlorine, phosgene and mustard gases) in the battlefield. International treaties (the 1925 Geneva Protocol, the 1975 Biological and Toxin Weapons Convention and the 1993 Chemical Weapons Convention) banned biological and chemical weapons. However, several countries are probably still engaged in their development. Hence, there is risk of these weapons being used in the future. This chapter will focus on neurotoxic weapons (e.g. nerve agents, chemical and biological neurotoxins, psychostimulants), which act specifically or preeminently on the central nervous system and/or the neuromuscular junction. Deeply affecting the function of the nervous system, these agents either have incapacitating effects or cause clusters of casualties who manifest primary symptoms of encephalopathy, seizures, muscle paralysis and respiratory failure. The neurologist should be prepared both to notice patterns of symptoms and signs that are sufficiently consistent to raise the alarm of neurotoxic attacks and to define specific therapeutic interventions. Additionally, extensive knowledge on neurotoxic syndromes should stimulate scientific research to produce more effective antidotes and antibodies (which are still lacking for most neurotoxic weapons) for rapid administration in aerosolized forms in the case of terrorist or warfare scenarios.

Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark.

LSD was introduced in psychiatry in the 1950s. Between 1960 and 1973, nearly 400 patients were treated with LSD in Denmark. By 1964, one homicide, two suicides and four suicide attempts had been reported. In 1986 the Danish LSD Damages Law was passed after complaints by only one patient. According to the Law, all 154 applicants received financial compensation for LSD-inflicted harm. The Danish State Archives has preserved the case material of 151 of the 154 applicants. Most of the patients suffered from severe side effects of the LSD treatment many years afterwards. In particular, two-thirds of the patients had flashbacks. With the recent interest in LSD therapy, we should consider the neurotoxic potential of LSD.

Neuropathic organophosphates: from Scrugham, Heim and Lorot to Jake leg paralysis.

Henry Scrugham (1811-1898), the father of triphenyl-phosphate, was a student of Alexander Williamson (1824-1904), Professor of analytical and practical chemistry at the University College London. Williamson using the approach perfected by Scurgham reacted phosphorus pentachloride with cresol (a mixture of ortho, para and meta isomers) thus obtaining tricresyl phosphate (TCP). The triesters of phenol, cresol and naphtol were prepared with a higher yield by Rudolf Heim (1861-1919) by their respective reaction with phosphorus oxychloride (POCl3). Heim is also the first one to obtain pure tri-o-cresyl phosphate (TOCP). In the meantime French pharmacist Jules Brissonnet (1859-1915) synthesized creosote phosphate (containing i.a. TOCP) and popularized its use in the treatment of pulmonary phthisis (tuberculosis). Camille Lorot (1872-1951) and others in France and Germany recognized the ability of creosote phosphate to induce polyneuropathies but this knowledge did not prevent the Ginger Jake epidemic (Jake leg) of the 1930s in the US. The Jake induced neuropathy was first recognized and described in Oklahoma City by a General Practitioner, Ephraim Goldfain (1894-1983). Soon thereafter Maurice Isadore Smith (1887-1951), a pharmacologist, and chemist Elias Elvove (1883-1962) identified TOCP in Jamaican ginger extract as the causative agent. We attempt to shed some light on the life and family of the less known chemists, pharmacists and physicians associated with the synthesis of neuropathic organophosphates and with the recognition of their toxicity.

Neuropathy target esterase (NTE): overview and future.

Neuropathy target esterase (NTE) was discovered by M.K. Johnson in his quest for the entity responsible for the striking and mysterious paralysis brought about by certain organophosphorus (OP) esters. His pioneering work on OP neuropathy led to the view that the biochemical lesion consisted of NTE that had undergone OP inhibition and aging. Indeed, nonaging NTE inhibitors failed to produce disease but protected against neuropathy from subsequently administered aging inhibitors. Thus, inhibition of NTE activity was not the culprit; rather, formation of an abnormal protein was the agent of the disorder. More recently, however, Paul Glynn and colleagues showed that whereas conventional knockout of the NTE gene was embryonic lethal, conditional knockout of central nervous system NTE produced neurodegeneration, suggesting to these authors that the absence of NTE rather than its presence in some altered form caused disease. We now know that NTE is the 6th member of a 9-protein family called patatin-like phospholipase domain-containing proteins, PNPLA1-9. Mutations in the catalytic domain of NTE (PNPLA6) are associated with a slowly developing disease akin to OP neuropathy and hereditary spastic paraplegia called NTE-related motor neuron disorder (NTE-MND). Furthermore, the NTE protein from affected individuals has altered enzymological characteristics. Moreover, closely related PNPLA7 is regulated by insulin and glucose. These seemingly disparate findings are not necessarily mutually exclusive, but we need to reconcile recent genetic findings with the historical body of toxicological data indicating that inhibition and aging of NTE are both necessary in order to produce neuropathy from exposure to certain OP compounds. Solving this mystery will be satisfying in itself, but it is also an enterprise likely to pay dividends by enhancing our understanding of the physiological and pathogenic roles of the PNPLA family of proteins in neurological health and disease, including a potential role for NTE in diabetic neuropathy.

A brief history of INA and ICOH SCNP: International Neurotoxicology Association and International Congress on Occupational Health Scientific Committee on Neurotoxicology and Psychophysiology.

Two international scientific societies dedicated to research in neurotoxicology and neurobehavioral toxicology are the International Neurotoxicology Association (INA) and the International Congress on Occupational Health International Scientific Committee on Neurotoxicology and Psychophysiology (ICOH SCNP). From June 5-10, 2011 these two societies held a joint conference in Xi'an China entitled the Xi'an International Neurotoxicology Conference, Neurotoxicity and Neurodegeneration: Local Effect and Global Impact. At the conference two featured talks presented a brief history of the two societies. This article is a synthesis and expansion of those two presentations. The history of INA and ICOH SCNP is described in relation to the antecedent events leading to the formation of the two societies, their parallel developments, the nature of the societies and their scientific conferences, and a brief description of some of their accomplishments. Together, the historical development of these two societies is an important component of the development of the scientific discipline of neurotoxicology.

Torvis oculis: occupational roots of behavioral neurotoxicology in the last two centuries and beyond.

Behavioral toxicology is an important discipline of toxicology that traces its roots back to the origin of psychology. A parallel development can be traced for behavioral toxicology and psychology, in that both were focused on the mind or behavior, as distinct from neurology, that recognized the brain as the ultimate target. Ancient physicians and non-medical authors incidentally described the effects of neurotoxic agents on mood. In the last two centuries, experimental psychology, behaviorism and behavioral pharmacology further developed the observation of behavior with scientific methodology. During the Industrial Revolution exposure to neurotoxicants became widespread in the western world and the consequent "psycho-organic syndrome" was likely to affect a large part of the working population. Occupational Medicine met behavioral toxicology in the 1960s. The assessment of the effects of exposure on behavior was achieved with specific tests for motor and cognitive functions, and computer technology could be used to control and analyze behavioral experiments. The contribution of this discipline became further important in the identification of early adverse effects, also from environmental and dietary exposure. The detection of behavioral changes can precede the detection of neural changes, which makes the assessment of behavior especially suitable for risk assessment. Neurobehavioral methodology has further developed in the latest years towards a global and integrated approach to the different life stages of individuals, from early life to old age.

[Development of neurobehavioral toxicology in the last century and its historical roots]. / Sviluppo della neuro-tossicologia comportomentale nell'ultimo secolo e sue radici storiche.

Behavioral neuro-toxicology traces his origins back to psychology and occupational medicine. Within the "De Morbis Artificum", Bernardino Ramazzini described the effects of exposure to neurotoxic agents on the workers'psychological sphere. In the following centuries, experimental psychology and neuropsychology represented the two main roots of behavioral neurotoxicology. This discipline emerged in the 1960' as integrated with occupational Medicine. The assessment of the effects of exposure on behavior was achieved with specific tests for motor and cognitive functions. These methods have been further developed in the following years toward a global and integrated approach to the different life stages of individuals.

Elementary, my dear Dr. Allen: the case of barium toxicity and Pa Ping.

OBJECTIVE: We aimed to review the English and Chinese literature on Pa Ping and to confirm by personal interview the story of how its pathogenesis was uncovered. BACKGROUND: In 1930, Dr. Alexander Stewart Allen noticed a pattern of illness arising in the region of Kiating, China. Area residents began presenting to local hospitals with nausea, vomiting, and diarrhea, and what emerged was a clinical picture of a gradual ascending paralysis that could result in death, termed Pa Ping. All 3 patients observed by Dr. Allen were male, had no family history of the disease, and had recently eaten before the onset of paralysis. Pa Ping developed in Dr. Allen himself, but he survived. METHODS: Medical literature was reviewed for primary sources. Interviews of living descendants and friends of the doctors in China and North America were conducted and information was corroborated by written records. RESULTS: Dr. Huang, with the National Central University College of Medicine, noticed a striking similarity between Pa Ping and familial periodic paralysis in 12 patients and reported 2 patients with Pa Ping treated with potassium citrate who experienced a reversal of the paralysis. Dr. K.T. Du analyzed meals of patients with Pa Ping seen by Dr. Zhe Tung and found barium in concentrations as high as 25.7%. This finding was confirmed by administering barium chloride to animals, which recapitulated the human syndrome. CONCLUSIONS: Although Dr. Huang had correctly noticed an underlying potassium depletion in patients with Pa Ping, the observations of Dr. Zhe Tung and Dr. K.T. Du ultimately established barium-induced hypokalemia as the underlying cause.

The first 83 and the next 83: perspectives on neurotoxicology.

This commentary depicts the author's history, and how it became interwoven with neurotoxicology. Born in 1925, most of his life spanned a century burdened with calamitous wars as well as revolutionary developments in science. Aviation played a large role in the century's wars and in the author's outlook on the world. He moved from a literary perspective, after his war experiences, to one governed by science, his earliest bent. During his career, which embodied the early development of both behavioral pharmacology and behavioral toxicology, he emphasized the critical need for precise measures, a point of view illustrated by his adoption of digital computer technology in 1962 as a means to secure such measures. The commentary also describes the author's views of some of the new directions open to neurotoxicology, such as the pursuit of questions about endocrine disruptors, countermeasures for brain aging, and epigenetics.

Neurology of acute organophosphate poisoning.

Acute organophosphate (OP) poisoning is one of the most common poisonings in emergency medicine and toxicological practice in some of the less-developed nations in South Asia. Traditionally, OP poisoning comes under the domain of emergency physicians, internists, intensivists, and toxicologists. However, some of the complications following OP poisoning are neurological and involve neurologists. The pathophysiological basis for the clinical manifestations of OP poisoning is inactivation of the enzyme, acetylcholinesterase at the peripheral nicotinic and muscarinic and central nervous system (CNS) nerve terminals and junctions. Nicotinic manifestations occur in severe cases and late in the course; these comprise of fasciculations and neuromuscular paralysis. There is a good correlation between the electrophysiological abnormalities and the severity of the clinical manifestations. Neurophysiological abnormalities characteristic of nicotinic junctions (mainly neuromuscular junction) dysfunction include: (1) single, supramaximal electrical-stimulus-induced repetitive response/s, (2) decrement-increment response to high frequency (30 Hz) repetitive nerve stimulation (RNS), and (3) decremental response to high frequency (30 Hz) RNS. Atropine ameliorates muscarinic manifestations. Therapeutic agents that can ameliorate nicotinic manifestations, mainly neuromuscular, are oximes. However, the evidence for this effect is inconclusive. This may be due to the fact that there are several factors that determine the therapeutic effect of oximes. These factors include: The OP compound responsible for poisoning, duration of poisoning, severity of poisoning, and route of exposure. There is also a need to study the effect of oximes on the neurophysiological abnormalities.

The role of psychopharmacology in the medical abuses of the Third Reich: from euthanasia programmes to human experimentation.

German psychiatry and pharmacology both enjoyed an extraordinary international reputation prior to the promulgation of the Third Reich. However, with the triumph of eugenic ideas and the imposition of a "racial hygiene" policy by the Nazi regime, various organs of the German health system saw themselves involved in a perverse system of social control, in which the illicit use of psychopharmacological tools became customary. In the present work, we review, from the historical perspective, the factors that helped to bring about this situation and we analyze the abuses (known and documented) committed through the specific use of psychotropic drugs during the Nazi period. Among such abuses we can identify the following illegitimate activities: the use of psychoactive drugs, mainly sedatives from the barbiturates family, in the different euthanasia programmes implemented by the Nazi authorities, in police activity and various types of repression, and for purely criminal and extermination purposes within the so-called "Final Solution"; psychopharmacological research on the mentally ill, without the slightest ethical requirements or legal justification; and the use of psychotropic agents in research on healthy subjects, recruited from concentration camps. Finally, we refer to the role of poisonous nerve agents (tabun, sarin and soman) as instruments of chemical warfare and their development by the German authorities. Many of these activities, though possibly only a small portion of the total - given the destruction of a great deal of documentation just before the end of World War II - came to light through the famous Nuremberg Trials, as well as through other trials in which specific persons were brought to justice unilaterally by individual Allied nations or by the authorities of the new German government after the War.

Historical neurotoxins: what we have learned from toxins of the past about diseases of the present.

Throughout history, humans have fallen victim to a variety of neurotoxins, with exposures coming in the form of tainted products, industrial pollution, drugs of abuse, and even the bread and water that sustain them. Despite this long and tumultuous history, neurotoxic outbreaks still occur with regular frequency. Although many difficulties currently exist in linking many of today's unexplained neurologic disorders to toxins, the past suggests a prominent role for neurotoxins in diseases (such as amyotrophic lateral sclerosis and PD), unexplained peripheral neuropathies, neurodevelopmental disorders, and many psychiatric disturbances.