Nodding syndrome: A role for environmental biotoxins that dysregulate MECP2 expression?

Nodding syndrome is an epileptic encephalopathy associated with neuroinflammation and tauopathy. This initially pediatric brain disease, which has some clinical overlap with Methyl-CpG-binding protein 2 (MECP2) Duplication Syndrome, has impacted certain impoverished East African communities coincident with local civil conflict and internal displacement, conditions that forced dependence on contaminated food and water. A potential role in Nodding syndrome for certain biotoxins (freshwater cyanotoxins plus/minus mycotoxins) with neuroinflammatory, excitotoxic, tauopathic, and MECP2-dysregulating properties, is considered here for the first time.

Lathyrism in Spain: Lessons from 68 publications following the 1936-39 Civil War.

After the end of the Spanish Civil War (1936-1939), an estimated 1,000 patients presented with lathyrism due to their excessive and prolonged consumption of grasspea (Lathyrus sativus L.) against the backdrop of poverty, drought, and famine. Based on 68 scientific communications between 1941 and 1962 by qualified medical professionals, the disease emerged in different geographical locations involving selective populations: (1) farmers from extensive areas of central Spain, traditionally producers and consumers of grasspea; (2) immigrants in the industrial belt of Catalonia and in the Basque Country, areas with little or no production of grasspea, which was imported from producing areas; (3) workers in Galicia, an area where the legume is neither produced nor consumed, who were seasonally displaced to high-production areas of grasspea in Castille; and (4) inmates of overcrowded postwar Spanish prisons. Original reports included failed attempts by Carlos Jiménez Díaz (1898-1967) to induce experimental lathyrism, the neuropathology of lathyrism in early stages of the disease in two patients, as reported by Carlos Oliveras de la Riva (1914-2007), and the special susceptibility of children to develop a severe form of lathyrism after relatively brief periods of consumption of the neurotoxic seed of L. sativus. In the Spanish Basque Country, L. cicera L. (aizkol) was cultivated exclusively as animal fodder. Patients who were forced to feed on this plant developed unusual manifestations of lathyrism, such as axial myoclonus and severe neuropsychiatric disorders, unknown in other regions of the country and previously unreported. The postwar epidemic of lathyrism in Spain represents the most extensively studied outbreak of this self-limiting but crippling upper motor neuron disease.

Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology via lifetime exposome research.

The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.

Preliminary seroprevalence study of neurotropic virus antibodies in Nodding syndrome.

Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition.

Lytico-bodig in Guam: Historical links between diet and illness during and after Spanish colonization.

This paper analyses documents on health and disease among Chamorro people during and after 333 years (1565-1898) of the Spanish claim to and occupation of Guam. Here, a complex neurodegenerative disease-known locally as lytico-bodig and medically as amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC)-reached hyperendemic proportions in the mid-twentieth century but then declined and is now disappearing. A tau-dominated polyproteinopathy, clinical phenotypes included amyotrophic lateral sclerosis (ALS or lytico), atypical parkinsonism with dementia (P-D or bodig), and dementia alone. A plausible etiology for lytico-bodig is consumption of flour derived from the incompletely detoxified seed of Cycas micronesica (fadang in Chamorro; Federico in Spanish), a poisonous gymnosperm that survives climatic extremes that can affect the island. Traditional methods for safe consumption appear to have been lost over the course of time since governors Francisco de Villalobos (1796-1862) and Felipe de la Corte (1855-1866) proposed banning consumption in view of its acute toxic effects. A death certificate issued in 1823 might suggest ALS/PDC in people dying with disability or impedidos, and premature aging and a short life was linked to food use of fadang in the mid-1850s (Guam Vital Statistics Report, 1823). During the Japanese occupation of Guam (1941-1944), Chamorro people took refuge in the jungle for months, where they relied on insufficiently processed fadang as a staple food. After World War II, traditional foods and medicines were subsequently replaced as islanders rapidly acculturated to North American life.

Direct and Indirect Neurotoxic Potential of Metal/Metalloids in Plants and Fungi Used for Food, Dietary Supplements, and Herbal Medicine.

Plants and mushrooms bioconcentrate metals/metalloids from soil and water such that high levels of potentially neurotoxic elements can occur in cultivated and wild species used for food. While the health effects of excessive exposure to metals/metalloids with neurotoxic potential are well established, overt neurological disease from prolonged ingestion of contaminated botanicals has not been recognized. However, the presence of metal elements may affect levels of botanical neurotoxins in certain plants and mushrooms that are established causes of acute and chronic neurological disease.

Case-Control Study of Nodding Syndrome in Acholiland: Urinary Multi-Mycotoxin Screening.

This case-control study adds to the growing body of knowledge on the medical, nutritional, and environmental factors associated with Nodding Syndrome (NS), a seizure disorder of children and adolescents in northern Uganda. Past research described a significant association between NS and prior history of measles infection, dependence on emergency food and, at head nodding onset, subsistence on moldy maize, which has the potential to harbor mycotoxins. We used LC-MS/MS to screen for current mycotoxin loads by evaluating nine analytes in urine samples from age-and-gender matched NS cases (n = 50) and Community Controls (CC, n = 50). The presence of the three mycotoxins identified in the screening was not significantly different between the two groups, so samples were combined to generate an overall view of exposure in this community during the study. Compared against subsequently run standards, α-zearalenol (43 ± 103 µg/L in 15 samples > limit of quantitation (LOQ); 0 (0/359) µg/L), T-2 toxin (39 ± 81 µg/L in 72 samples > LOQ; 0 (0/425) µg/L) and aflatoxin M1 (4 ± 10 µg/L in 15 samples > LOQ; 0 (0/45) µg/L) were detected and calculated as the average concentration ± SD; median (min/max). Ninety-five percent of the samples had at least one urinary mycotoxin; 87% were positive for two of the three compounds detected. While mycotoxin loads at NS onset years ago are and will remain unknown, this study showed that children with and without NS currently harbor foodborne mycotoxins, including those associated with maize.

Kampo medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex): Postscript and Historical Footnote.

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) is a disappearing neurodegenerative disease in three former high-incidence foci of the U.S. territory of Guam, Papua-Indonesia (New Guinea) and Kii Peninsula, Honshu Island, Japan (Muro disease). We report additional data that associate medicinal use of cycad seed to Muro disease in the southern Kozagawa focus of ALS/PDC. In the other two ALS/PDC-affected populations, cycad seed was used as a traditional topical medicine in New Guinea and Guam and, additionally, for food on Guam.

Western Pacific ALS-PDC: Evidence implicating cycad genotoxins.

Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) is a disappearing neurodegenerative disorder of apparent environmental origin formerly hyperendemic among Chamorros of Guam-USA, Japanese residents of the Kii Peninsula, Honshu Island, Japan and Auyu-Jakai linguistic groups of Papua-Indonesia on the island of New Guinea. The most plausible etiology is exposure to genotoxins in seed of neurotoxic cycad plants formerly used for food and/or medicine. Primary suspicion falls on methylazoxymethanol (MAM), the aglycone of cycasin and on the non-protein amino acid ß-N-methylamino-L-alanine, both of which are metabolized to formaldehyde. Human and animal studies suggest: (a) exposures occurred early in life and sometimes during late fetal brain development, (b) clinical expression of neurodegenerative disease appeared years or decades later, and (c) pathological changes in various tissues indicate the disease was not confined to the CNS. Experimental evidence points to toxic molecular mechanisms involving DNA damage, epigenetic changes, transcriptional mutagenesis, neuronal cell-cycle reactivation and perturbation of the ubiquitin-proteasome system that led to polyproteinopathy and culminated in neuronal degeneration. Lessons learned from research on ALS-PDC include: (a) familial disease may reflect common toxic exposures across generations, (b) primary disease prevention follows cessation of exposure to culpable environmental triggers; and (c) disease latency provides a prolonged period during which to intervene therapeutically. Exposure to genotoxic chemicals ("slow toxins") in the early stages of life should be considered in the search for the etiology of ALS-PDC-related neurodegenerative disorders, including sporadic forms of ALS, progressive supranuclear palsy and Alzheimer's disease.

Kampo medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex).

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-dementia Complex (ALS/PDC) is a disappearing neurodegenerative disease in three former high-incidence foci of Guam-USA, Papua-Indonesia and Kii Peninsula, Honshu Island, Japan. The latter includes two distinct ALS/PDC-affected regions (Hohara and Kozagawa), where the disorder is known as Muro disease. In Hohara, oral exposure to plant (cycad) neurotoxins used in traditional medical practice has been linked previously to Muro disease. We report new observations that link Kampo medicine to Muro disease in the southern Kozagawa focus. Oral exposure to cycad seed toxins is associated with all three foci of Western Pacific ALS/PDC.

Surgical Confusions in Ophthalmology: Description, Analysis, and Prevention of Errors from 2006 through 2017.

PURPOSE: To characterize surgical confusions in ophthalmology to determine their incidence, root causes, and impact on patients and physicians. DESIGN: Retrospective cohort study of errors in ophthalmic surgical procedures between January 1, 2006, and December 31, 2017. PARTICIPANTS: One hundred forty-three cases involving surgical confusions. METHODS: Cases were identified by the Ophthalmic Mutual Insurance Company from closed case files and by the New York State Health Department from the New York Patient Occurrence Reporting and Tracking program that identified the surgical confusions. MAIN OUTCOME MEASURES: Incidence and impact by intended surgery, error type, and root cause as well as preventability by the Universal Protocol. RESULTS: Of the 143 cases of surgical confusions identified, 92 cases (64.3%) were deemed preventable by the Universal Protocol. Approximately two thirds, 95 cases (66.4%), were cases of incorrect implants being used during cataract surgery (cataract extraction and intraocular lens implantation), of which 33 cases (34.7%) were not preventable by the Universal Protocol. Wrong eye blocks or anesthesia accounted for 20 cases (14.0%), incorrect eye procedures accounted for 10 cases (7.00%), incorrect refractive surgery measurements accounted for 6 cases (4.20%), incorrect patient or procedure accounted for 5 cases (3.50%), incorrect intraocular gas concentration accounted for 4 cases (2.80%), and incorrect medication in surgery accounted for 3 cases (2.10%). The most common root cause of confusion was an inadequately performed time out, which was responsible for nearly one third of all surgical confusions, 46 cases (32.2%). Incorrect lens orders or calculations before surgery (so-called upstream errors) were the second most common cause of surgical confusion, involving 31 cases (21.7%). The average legal indemnity for incorrect implant during cataract surgery was $57 514 (United States dollars). The average indemnity for incorrect refractive surgery measurement was $123 125, that for incorrect eye procedure was $50 000, and that for incorrect gas concentration was $220 844. CONCLUSIONS: Most surgical confusions could have been prevented by following the Universal Protocol properly. However, upstream errors, originating in the clinic or office before surgery, and ineffective communication during time outs suggest a need for modification of the Universal Protocol.

Cycad ß-N-methylamino-L-alanine (BMAA), methylazoxymethanol, genotoxicity, and neurodegeneration.

Cycad-associated neurodegenerative disease is more strongly correlated with the gymnosperm's major neurotoxin cycasin (methylazoxymethanol glucoside) than with the minor neurotoxin ß-N-methylamino-L-alanine (L-BMAA).

A real-time medical cartography of epidemic disease (Nodding syndrome) using village-based lay mHealth reporters.

BACKGROUND: Disease surveillance in rural regions of many countries is poor, such that prolonged delays (months) may intervene between appearance of disease and its recognition by public health authorities. For infectious disorders, delayed recognition and intervention enables uncontrolled disease spread. We tested the feasibility in northern Uganda of developing real-time, village-based health surveillance of an epidemic of Nodding syndrome (NS) using software-programmed smartphones operated by minimally trained lay mHealth reporters. METHODOLOGY AND PRINCIPAL FINDINGS: We used a customized data collection platform (Magpi) that uses mobile phones and real-time cloud-based storage with global positioning system coordinates and time stamping. Pilot studies on sleep behavior of U.S. and Ugandan medical students identified and resolved Magpi-programmed cell phone issues. Thereafter, we deployed Magpi in combination with a lay-operator network of eight mHealth reporters to develop a real-time electronic map of child health, injury and illness relating to NS in rural northern Uganda. Surveillance data were collected for three consecutive months from 10 villages heavily affected by NS. Overall, a total of 240 NS-affected households and an average of 326 children with NS, representing 30 households and approximately 40 NS children per mHealth reporter, were monitored every week by the lay mHealth team. Data submitted for analysis in the USA and Uganda remotely pinpointed the household location and number of NS deaths, injuries, newly reported cases of head nodding (n = 22), and the presence or absence of anti-seizure medication. CONCLUSIONS AND SIGNIFICANCE: This study demonstrates the feasibility of using lay mHealth workers to develop a real-time cartography of epidemic disease in remote rural villages that can facilitate and steer clinical, educational and research interventions in a timely manner.

Environmental, dietary and case-control study of Nodding Syndrome in Uganda: A post-measles brain disorder triggered by malnutrition?

Nodding Syndrome (NS) is an epileptic encephalopathy characterized by involuntary vertical head nodding, other types of seizures, and progressive neurological deficits. The etiology of the east African NS epidemic is unknown. In March 2014, we conducted a case-control study of medical, nutritional and other risk factors associated with NS among children (aged 5-18years) of Kitgum District, northern Uganda (Acholiland). Data on food availability, rainfall, and prevalent disease temporally related to the NS epidemic were also analyzed. In NS Cases, the mean age of reported head nodding onset was 7.6years (range 1-17years). The epidemiologic curve of NS incidence spanned 2000-2013, with peaks in 2003 and 2008. Month of onset of head nodding was non-uniform, with all-year-aggregated peaks in April and June when food availability was low. Families with one or more NS Cases had been significantly more dependent on emergency food and, immediately prior to head nodding onset in the child, subsistence on moldy plant materials, specifically moldy maize. Medical history revealed a single significant association with NS, namely prior measles infection. NS is compared with the post-measles disorder subacute sclerosing panencephalitis, with clinical expression triggered by factors associated with poor nutrition.

Seeking environmental causes of neurodegenerative disease and envisioning primary prevention.

Pathological changes of the aging brain are expressed in a range of neurodegenerative disorders that will impact increasing numbers of people across the globe. Research on the causes of these disorders has focused heavily on genetics, and strategies for prevention envision drug-induced slowing or arresting disease advance before its clinical appearance. We discuss a strategic shift that seeks to identify the environmental causes or contributions to neurodegeneration, and the vision of primary disease prevention by removing or controlling exposure to culpable agents. The plausibility of this approach is illustrated by the prototypical neurodegenerative disease amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). This often-familial long-latency disease, once thought to be an inherited genetic disorder but now known to have a predominant or exclusive environmental origin, is in the process of disappearing from the three heavily affected populations, namely Chamorros of Guam and Rota, Japanese residents of Kii Peninsula, Honshu, and Auyu and Jaqai linguistic groups on the island of New Guinea in West Papua, Indonesia. Exposure via traditional food and/or medicine (the only common exposure in all three geographic isolates) to one or more neurotoxins in seed of cycad plants is the most plausible if yet unproven etiology. Neurotoxin dosage and/or subject age at exposure might explain the stratified epidemic of neurodegenerative disease on Guam in which high-incidence ALS peaked and declined before that of PD, only to be replaced today by a dementing disorder comparable to Alzheimer's disease. Exposure to the Guam environment is also linked to the delayed development of ALS among a subset of Chamorro and non-Chamorro Gulf War/Era veterans, a summary of which is reported here for the first time. Lessons learned from this study and from 65 years of research on ALS-PDC include the exceptional value of initial, field-based informal investigation of disease-affected individuals and communities, the results of which can provide an invaluable guide to steer cogent epidemiological and laboratory-based research.