Rett syndrome: the Brazilian contribution to the gene discovery / Síndrome de Rett: a contribuição brasileira para a descoberta do gene

ABSTRACT A brief history of the syndrome discovered by Andreas Rett is reported in this paper. Although having been described in 1966, the syndrome was only recognized by the international community after a report by Hagberg et al. in 1983. Soon, its importance was evident as a relatively frequent cause of severe encephalopathy among girls. From the beginning it was difficult to explain the absence of male patients and the almost total predominance of sporadic cases (99%), with very few familial cases. For these reasons, it was particularly difficult to investigate this condition until 1997, when a particular Brazilian family greatly helped in the final discovery of the gene, and in the clarification of its genetic mechanism. Brief references are made to the importance of the MECP2 gene, 18 years later, as well as to its role in synaptogenesis and future prospects.

RESUMO Uma breve história de uma síndrome neurológica descoberta por Andreas Rett é relatada neste artigo. Embora tenha ocorrido em 1966, a síndrome só foi reconhecida pela comunidade internacional após um relato de Hagberget al, em 1983. Logo, sua importância ficou evidente como causa relativamente frequente de encefalopatia grave entre as crianças do sexo feminino. Desde o início, foi difícil explicar a ausência de envolvimento de pacientes do sexo masculino e a quase absoluta preponderância de casos esporádicos (99%), com muitos poucos casos familiares. Por essas razões, foi difícil investigar essa condição até 1997, quando uma família brasileira em particular ajudou muito na descoberta final do gene e no esclarecimento de seu mecanismo genético. São feitas referências sucintas à importância do gene MECP2, dezoito anos depois, bem como ao seu papel na sinaptogênese e nas perspectivas futuras.

History of Subcortical Cognitive Impairment.

The representation of cognitive function in the cerebral cortex has a long and cherished history, but much evidence also supports a critical role of subcortical structures in the operations of cognition. The idea of subcortical dementia, first proposed in 1932 and substantially expanded in the 1970s, is the most prominent formulation intended to capture the phenomenology of cognitive impairment attributable to subcortical involvement. Despite criticism highlighting its imprecision, subcortical dementia has endured as a useful general concept assisting the classification of dementia syndromes based on the primary site(s) of neuropathology. As neuroscientific knowledge expanded with the advent of modern structural and functional neuroimaging, a more detailed understanding of the contributions of specific subcortical regions emerged, such that the cognitive affiliations of the basal ganglia, thalamus, cerebellum, brainstem, and white matter are all better defined. Important advances have been made by the study of both neurodegenerative diseases and focal lesions. Today, the complex admixture of cortical and subcortical foundations of cognition is increasingly well appreciated, and has been conceptually organized within the broadly inclusive notion of distributed neural networks. These networks are thought to integrate cortical and subcortical gray and white matter structures throughout the brain into functional neuronal ensembles subserving various domains of cognition. In this light, specific disorders of subcortical regions produce cognitive sequelae that can be usefully analyzed within the context of networks that involve key cortical regions as well. The study of subcortical contributions to cognition has been highly informative in expanding neurobehavioral thinking to include regions beyond the cerebral cortex, adding nuance and sophistication to the conceptualization of brain-behavior relationships.

History of Dementia.

The term dementia derives from the Latin root demens, which means being out of one's mind. Although the term "dementia" has been used since the 13th century, its mention in the medical community was reported in the 18th century. Even though the Greeks postulated a cerebral origin, the concept was not restricted to senile dementia and included all sorts of psychiatric and neurological conditions leading to psychosocial consequences. In the 19th century, individuals with dementia were recognized as patients, deserving medical care from specialists called alienists, and senile dementia became a medical disease. Subsequently, progresses in neuropathology allowed its fragmentation into different neuropathological conditions. Senile dementia was considered as a distinct entity from Alzheimer's seminal case published in 1906, and was first attributed to a vascular origin. However, from the late 1960s and for 20 subsequent years, Alzheimer's disease became the prototypical senile dementia. Only recently, the term dementia was abandoned for major neurocognitive disorder and the heterogeneity of the syndrome acknowledged again at the phenotypical and molecular levels. We hope a better understanding of this fascinating history will improve scientific research and impose humility towards the complex underpinnings of age-related cognitive decline.

History of Neuropsychological Assessment.

This chapter presents a historical overview of observations, instruments, and approaches in the area of neuropsychological assessment. In the 17th and 18th century literature dealing especially with language disorders following a brain disorder, one finds observations of physicians of striking dissociations of mental faculties that were impaired while others remained intact. Around the middle of the 19th century, neuropsychiatrists like Carl Wernicke began to develop procedures for assessing more specific components of mental functioning. German physicians, Conrad Rieger and Theodor Ziehen, seem to have developed the first neuropsychological test batteries. Kurt Goldstein, inspired by the rising Gestalt theory, argued that not the test score but the strategy used by a patient to perform a task is important. Alexander Luria also promoted an approach to assessment that was mainly based on subjective judgment. Studies on individual differences led to the development of an intelligence test battery by Alfred Binet. This battery was later transformed into the Army Alpha and Army Beta tests for selecting soldiers. Components of these intelligence tests have survived in the test kit of the modern neuropsychologist. This tradition also stimulated the development of psychometric analysis of tests. Two pioneers in the field of neuropsychological assessment were Shepherd Ivory Franz, favoring a clinical approach, and Ward Halstead, stimulating a strongly psychometric-based approach. The evaluation of language disorders has always been a specific area, requiring its own set of tests. The first comprehensive language battery was compiled by Bastian. Around the middle of the 20th century, when the localization of function approach had been rejected, neurologists preferred to examine language disorders clinically, using a battery that evaluated speech, comprehension, reading, and writing.

The development and evolution of "cerebral thermometry": Clinical applications of a nineteenth-century approach to cerebral localization and neurological diagnosis.

Surface thermometers were developed in the latter half of the nineteenth century. In 1877, Broca, already famous for his contributions to the cerebral localization of nonfluent aphasia, presented his first clinical observations on cranial surface temperatures: In two cases, cranial surface temperatures were decreased over a middle cerebral artery infarction, and increased in surrounding areas, which Broca attributed to "compensatory hyperaemia." As Broca made apparent in a later report in 1879, he had used a "thermometric crown," an apparatus consisting of six to eight large-reservoir mercury thermometers strapped against the head. Following Broca's report, American neurologists reported cases in which cranial surface temperatures were increased either locally over a superficial brain tumor or globally with a cerebral abscess. Despite promising anecdotal reports, contemporaries recognized that significant technical and practical problems limited its accuracy, reliability, and clinical utility. Advocates never demonstrated that this technology provided significant marginal benefit to the medical history and physical examination. The technique fell out of fashion before 1900, though some early advocates promoted it into the early twentieth century. It was ultimately replaced by more effective technologies for cerebral localization and neurological diagnosis.

The development and evolution of "cerebral thermometry": The physiology underlying a nineteenth-century approach to cerebral localization and neurological diagnosis.

Surface thermometers were developed in the latter half of the nineteenth century. From the 1850s through the 1880s, collaborations between physicians, research scientists, and instrument makers produced clear improvements in the technology to measure cranial surface temperatures, with development of self-registering mercury surface thermometers resistant to pressure and little influenced by ambient temperature, apparatus for recording cranial surface temperatures from multiple stations simultaneously, and development of thermoelectric apparatus. Physiologic studies of cranial surface thermometry were conducted over a quarter century from 1861 to 1886. Beginning in the 1860s Albers in Bonn, Germany, and Lombard at Harvard and later in England systematically investigated surface temperatures on the head using surface thermometers and thermoelectric apparatus; they demonstrated that head temperatures were variable over time and across individuals and were not clearly influenced by thinking or muscular contraction but were influenced by ambient air temperature. In 1880 Amidon in the United States claimed that cranial surface thermometry during exertion produced localized increases in surface temperature on the contralateral scalp in a specific pattern ("external motive areas") indicating underlying brain areas responsible for each movement. Amidon's results were not reproduced by experienced physiologists in England or France. Contemporaries recognized that significant technical and practical problems limited the accuracy and reliability of cranial surface thermometry. Physiological studies of cranial surface thermometry ended in the mid 1880s, although some clinicians who were early advocates promoted its use in clinical contexts into the early twentieth century.

Rett syndrome: the Brazilian contribution to the gene discovery.

OBJECTIVE: A brief history of the syndrome discovered by Andreas Rett is reported in this paper. METHODS: Although having been described in 1966, the syndrome was only recognized by the international community after a report by Hagberg et al. in 1983. Soon, its importance was evident as a relatively frequent cause of severe encephalopathy among girls. CONCLUSION: From the beginning it was difficult to explain the absence of male patients and the almost total predominance of sporadic cases (99%), with very few familial cases. For these reasons, it was particularly difficult to investigate this condition until 1997, when a particular Brazilian family greatly helped in the final discovery of the gene, and in the clarification of its genetic mechanism. RESULTS: Brief references are made to the importance of the MECP2 gene, 18 years later, as well as to its role in synaptogenesis and future prospects.

Dementia and Change of Style: Willem de Kooning - Obliteration of Disease Patterns?

The studies on the relation between artistic production, especially visual art, and brain function gave a basis to the development of neuroesthetics. Most of the information on brain artistic creativity comes from studies on brain disease in well-established visual artists. Brain disease may cause change, dissolution, or emergence of artistic creativity. The visual artistic production may become impaired in individuals with a variety of brain diseases, including focal and generalised disorders of sudden and slowly progressive onset. In addition to that, neurological disorders may add content into visual art production, even becoming the artistic theme. Here, we discuss the particular case of abstract expressionist Willem de Kooning and the evolution of his artistic production in the context of his neurodegenerative illness. The change of de Kooning's artistic style has been the subject of many reviews, and the main focus of this paper is on artistic style across his prolific artistic career in the context of his progressive neurological condition, which he developed in his late years, and his long history of alcohol addiction. There are conflicting data from the literature on the effect of his neurological condition and clear cognitive decline on his artistic output, with preservation of recognition and the quality of his art. Hence, two pertinent questions relate to how he was able to maintain his output despite his cognitive decline, and how his condition could have affected his work.

'Brain Disorders', by Henry Calderwood (1879).

Henry Calderwood, a nineteenth-century Scottish philosopher interested in madness, published in 1879 an important work on the interaction between philosophy of mind, the nascent neurosciences and mental disease. Holding a spiritual view of the mind, he considered the phrase 'mental disease' (as Feuchtersleben had in 1845) to be but a misleading metaphor. His analysis of the research work of Ferrier, Clouston, Crichton-Browne, Maudsley, Tuke, Sankey, etc., is detailed, and his views are correct on the very limited explanatory power that their findings had for the understanding of madness. Calderwood's conceptual contribution deserves to be added to the growing list of nineteenth-century writers who started the construction of a veritable 'philosophy of alienism' (now called 'philosophy of psychiatry').

Howard B. Eichenbaum (1947-2017).

Presents an obituary of Howard B. Eichenbaum (1947-2017). Eichenbaum, a world leader in the study of memory and the brain, died in Boston, Massachusetts, on July 21, 2017, at age 69, following recent spine surgery. Eichenbaum was a hugely creative and integrative scientist whose work combined cognitive and lesion analyses with high-density neuronal recordings, providing insights into brain computations and representations that help bridge psychological and physiological mechanisms of memory. His theories and original and elegant experiments in animals have greatly advanced our knowledge of the nature and brain mechanisms of memory in animals and humans alike. (PsycINFO Database Record

Richard Bright's observations on diseases of the nervous system due to inflammation.

This study examines case reports of brain diseases attributed to inflammation in Richard Bright's Reports of Medical Cases, Volume II. The rationale for the belief that these cases were due to inflammation is discussed in light of theories of inflammation that were current in Bright's time. The consequences of these theories for the therapy of brain diseases are evaluated. The value of Bright's reports lies in the accuracy of the descriptions of a number of brain diseases, featuring descriptions of symptoms or conditions that were novel or not well known in the early nineteenth century. They provided a conception of diseases that constituted "typical condition of many patients," rather than "disorderly condition of a particular patient." Many cases are illustrated by remarkable images of pathological specimens.

History, Current Situation, and Future Development of Endoscopic Neurosurgery in China.

OBJECTIVE: During the past few decades, Chinese endoscopic neurosurgery has rapidly developed in synchrony with the rest of the world. The aim of this article is to review the development of Chinese endoscopic neurosurgery, including its birth, growth, current situation, and prospects. METHODS: The history of Chinese endoscopic neurosurgery development can be divided into 3 stages: cognition and initial stage (1964-1995), exploration and maturity stage (1995-2006), and rapid development and promotion stage (2006-present). RESULTS: In the first stage, we mainly began to become aware of endoscopic neurosurgery from the translation and review of literature. In the mid to late 1990s, Chinese neurosurgery pioneers began using neuroendoscopic techniques. In the following decade, many leading neurosurgeons made persistent efforts to push the development of Chinese endoscopic neurosurgery forward, focusing on advocating for and promoting and popularizing neuroendoscopic technology. In the rapid development and promotion stage, many representative national and regional neurosurgical centers became skilled and efficient in the application of neuroendoscopic technology and became new advocates of the technology. The number of cases, level of technology, and treatment effectiveness are gradually nearing international standards. However, future development requires promotion of balanced development to decrease regional disparities, further strengthen international exchanges, follow the latest developments, and constantly innovate for continuous improvement. CONCLUSIONS: Following the dramatic efforts of several pioneers, development of Chinese endoscopic neurosurgery has been considerable, and it has become an important component of neurosurgery worldwide.

Ethnopharmacology in the fight against Plasmodium parasites and brain disorders: In memoriam of Philippe Rasoanaivo.

Prof. Philippe Rasoanaivo was a highly dedicated and brilliant scientist in the field of ethnopharmacology. He worked for the Institut Malgache de Recherches Appliquées and the University of Antananarivo, Madagascar. His research was mainly focused on the endemic medicinal and aromatic plants used by traditional healers in Madagascar against a range of parasites, with special reference to Plasmodium spp. In this Editorial, we resumed the key findings of his research activity, with special reference to the discovery of alkaloids that markedly enhance the action of chloroquine against malaria parasites.

[German neurology and neurologists during the Third Reich: brain research and "euthanasia"]. / Neurologie und Neurologen in der NS-Zeit: Hirnforschung und "Euthanasie".

The connection between systematic killing of the mentally ill and disabled, euphemistically called "euthanasia" in the National Socialism ideology, and German brain research has been thoroughly investigated and in detail; however, the impact of this criminal nexus on the image and self-perception of German neurologists as well as the status of neurology as a medical discipline is still the subject of controversial debates.Between 1939 and 1945 the Kaiser Wilhelm Institute (KWI) in Berlin along with other research centres were insofar enmeshed in the "euthanasia" program as brains of killed patients were dissected in the guise of "concomitant research" in order to generate medical knowledge. Affected were mainly individuals suffering from oligophrenia, early childhood brain atrophy, cerebral palsy and epilepsy. According to current historical research, collegial networks were instrumental in receiving brains of killed patients. Furthermore, civil research units were supplemented by military ones at the KWI. These, too, were concerned with the collection of medical knowledge, for instance on injuries of the brain and spinal cord. The historical approach to consider the Nazi organizations and medicine as "resources for each other" seems, therefore, at least in part applicable to neurology.

Mythology and Neurosurgery.

Myths are the keystone of mythology. They are interpretations of events that have been told as stories and legends for thousands of years, inherited from generation to generation, and have reached the present day. Although most myths are considered figments of the imagination or fictitious legends, all of them contain references to facts from the time they occurred. Mythology, which is a collection of figments of imagination concerning nature and human beings, is a product of human effort to perceive, explain, and interpret the universe and the world, much like science. The interaction between mythology and science dates back to the early days of civilization. Mythology, a reflection of human creativity, is extensively used in modern science, particularly in a terminological context. This article aims to reveal the texture of mythology in neurosurgery, by analyzing the birth of medicine in mythology; heroes such as Apollo and Asklepios, the gods of healing and medicine, as well as Hygieia, the goddess of health and hygiene; and mythological terms and phrases such as Achilles tendon, atlas vertebra, gigantism, priapism syndrome, hippocampus, lethargy, syrinx, and arachnoid. Through the use of symbols, mythology has attempted to explain several subjects, such as human nature, disease, birth, and death. In this respect, mythology and medicine dance arm in arm, and this dance has been going on for centuries. As a result, mythology has manifested itself in many fields within medicine, either anatomically or by giving names to various diseases.

Our first decade of experience in deep brain stimulation of the brainstem: elucidating the mechanism of action of stimulation of the ventrolateral pontine tegmentum.

The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region.