The Story of Intracerebral Hemorrhage: From Recalcitrant to Treatable Disease.

This invited special report is based on an award presentation at the World Stroke Organization/European Stroke Organization Conference in November of 2020 outlining progress in the acute management of intracerebral hemorrhage (ICH) over the past 35 years. ICH is the second most common and the deadliest type of stroke for which there is no scientifically proven medical or surgical treatment. Prospective studies from the 1990s onward have demonstrated that most growth of spontaneous ICH occurs within the first 2 to 3 hours and that growth of ICH and resulting volumes of ICH and intraventricular hemorrhage are modifiable factors that can improve outcome. Trials focusing on early treatment of elevated blood pressure have suggested a target systolic blood pressure of 140 mm Hg, but none of the trials were positive by their primary end point. Hemostatic agents to decrease bleeding in spontaneous ICH have included desmopressin, tranexamic acid, and rFVIIa (recombinant factor VIIa) without clear benefit, and platelet infusions which were associated with harm. Hemostatic agents delivered within the first several hours have the greatest impact on growth of ICH and potentially on outcome. No large Phase III surgical ICH trial has been positive by primary end point, but pooled analyses suggest that earlier ICH removal is more likely to be beneficial. Recent trials emphasize maximization of clot removal and minimizing brain injury from the surgical approach. The future of ICH therapy must focus on delivery of medical and surgical therapies as soon as possible if we are to improve outcomes.

Stroke: a modern history.

Prevention and treatment of stroke has changed substantially since the time of Franklin Delano Roosevelt who died of an intracerebral hemorrhage in 1945. As the understanding of stroke pathophysiology advanced, the beneficial effects of antiplatelet and anticoagulant drugs were recognized. Imaging of blood vessels by angiography made surgical therapies possible. Later noninvasive computerized tomography and magnetic resonance imaging distinguished hemorrhagic from ischemic stroke and gave new insight into stroke mechanisms. Stroke prevention became possible by selective management of stroke risk factors. Thrombolytics introduced 15 years ago provided the first actual treatment of ischemic stroke. The field of stroke continues to advance as medical and surgical treatments are refined and indications made clear, organized systems of care become standard, and new imaging techniques and endovascular therapies are developed.

Preservation of cell structures in a medieval infant brain: a paleohistological, paleogenetic, radiological and physico-chemical study.

Cerebral tissues from archaeological human remains are extremely rare findings. Hereby, we report a multidisciplinary study of a unique case of a left cerebral hemisphere from a 13th century AD child, found in north-western France. The cerebral tissue-reduced by ca. 80% of its original weight-had been fixed in formalin since its discovery. However, it fully retained its gross anatomical characteristics such as sulci, and gyri; the frontal, temporal and occipital lobe as well as grey and white matter could be readily recognised. Neuronal remains near the hippocampus area and Nissl bodies from the motor cortex area were observed (Nissl, Klüver-Barrera staining). Also, computed tomography (CT) and magnetic resonance imaging (T1, proton density, ultra short echo time sequences) were feasible. They produced high quality morpho-diagnostic images. Both histological and radiological examinations could not confirm the pathologist's previously suggested diagnosis of cerebral haemorrhage as the cause of death. Reproducible cloned mtDNA sequences were recovered from the skeleton but not from the brain itself. This was most likely due to the combined effect of formaldehyde driven DNA-DNA and/or DNA-protein cross-linking, plus hydrolytic fragmentation of the DNA. The chemical profile of the brain tissue, from gas-chromatography/mass-spectroscopy analysis, suggested adipocerous formation as the main aetiology of the mummification process. The hereby presented child brain is a unique paleo-case of well-preserved neuronal cellular tissue, which is a conditio sine qua non for any subsequent study addressing wider perspectives in neuroscience research, such as the evolution of brain morphology and pathology.

Did Jean-Martin Charcot contribute to stroke?

Stroke was never identified as a significant, autonomous field of activity of the emerging school of neurology at La Salpêtrière, which developed after the appointment of Jean-Martin Charcot (1825-1893) during the last days of 1861. However, stroke was already present in Charcot's first paper (1851), which dealt with a case of multiple organ cardiac embolism, including middle cerebral artery infarction, at a time when the studies of Rudolf Virchow on thromboembolism were unknown in France. A few years later, Charcot made a still up-to-date description of vascular intermittent claudication, which had only been reported in the horse. In the 1860s, Charcot and his pupils presented several major works dealing with cerebrovascular disease, including famous studies on miliary aneurysms in cerebral hemorrhage. This work was done with Charles Bouchard, at the time Charcot's 'interne', but who would become one of his 'political' opponents 2 decades later, when in 1892, as president of the 'agrégation' jury, he rejected the professorship application of 4 protégés of Charcot, including Joseph Babinski and Georges Gilles de la Tourette. Further work on cerebrovascular disease by Charcot included histological studies of brain 'softening', paraneoplastic cerebral arterial occlusion and consequences of stroke (e.g. arthropathies, vegetative changes, contractures and abnormal movements). Brain localization, one of Charcot's major neurological topics, was also largely based on stroke case studies. Charcot's work on stroke remains poorly recognized, but it demonstrates his unique skills in stimulating scientific work in younger colleagues, many of whom subsequently became major figures of neurology and psychiatry.

A Century of Germinal Matrix Intraventricular Hemorrhage in Autopsied Premature Infants: A Historical Account.

The care of premature infants in the 20th century is remarkable for technical advances that have dramatically improved survival, but little is known about temporal changes in the neuropathology of the premature infant over this time frame. We hypothesize that the autopsy rate of germinal matrix hemorrhage changed in the 20th century relative to combined influences of clinical interventions that were both harmful and helpful. We examined germinal matrix hemorrhage with intraventricular hemorrhage (GMH-IVH) in 345 premature infants (gestational age 25-36 weeks) autopsied at Boston Children's Hospital from 1914 to 2015. There was a median of 19 cases/decade (range 7-68). Over the course of the study median gestational age decreased from 33 to 27 gestational weeks (P<0.001), and median postnatal survival increased from 2 to 26 days (P=0.02). The incidence of GMH-IVH increased from 4.7% before 1960 to 50.0% from 1975 to 1980, and then decreased to 12.5% after 2005 (P<0.001). The incidence of GMH-IVH increased >3-fold around the time of the introduction of positive pressure ventilation into premature intensive care in the mid-1960s. The increased incidence of GMH-IVH in the 1970s-1980s likely reflects respiratory and hemodynamic imbalances complicating mechanical ventilation. We speculate that the subsequent decreased incidence of GMH-IVH likely reflects stabilization of respiratory function with improvements in ventilators and in ventilator management beginning in the 1970s and the use of surfactant and antenatal steroids in the 1980s.

The pathobiography and death of Wolfgang Amadeus Mozart: from legend to reality.

Mozart, perhaps one of the greatest geniuses of modern age, died mysteriously at the age of 35 in Vienna in 1791. The causes of his death are still somewhat obscure and debated since we do not have any documentation acceptable by current scientific standards. Inevitably, the conclusions reached are highly debatable. In the present article the various interpretations of Mozart's death are taken into consideration-from his possible poisoning to causes of death more acceptable by the present diagnostic criteria. We suggest that the terminal cause of death was brain hemorrhaging or stroke, complicated by broncopneumonia and associated with renal failure induced by proliferative glomerulonephritis and glomerulosclerosis.

Brain stem hemorrhage: historical perspective.

Brain stem hemorrhage was first recorded in 1812. Its origin has been the subject of much study and experimentation. We review the studies that stress mechanical forces because dynamic axial distortion of the brain stem is a major factor in the physiology and pathology of the central nervous system.

The death of Sir Thomas Stamford Raffles (1781-1826).

The authors reviewed a rare autopsy report of Sir Thomas Stamford Raffles and offer a fresh interpretation of the cause of his death, with illustrations on the implied findings.

[Vascular attacks]. / Accidents vasculaires.

The present paper is aimed at presenting an overview of the studies on cerebrovascular diseases made by Charcot and his collaborators and later by the successive Professors in the Chair. The significance of studies from abroad is also briefly reviewed. Charcot's major interest in the field was cerebral haemorrhage and the evolution of the ideas about the aneurysms of Charcot-Bouchard is reviewed. During Charcot's Professorship, Henri Duret gave one of the first modern anatomical studies of the cerebral arteries. The study of lacunes was one among numerous important contributions of Pierre Marie to Neurology. Later the works of Charles Foix and his collaborators on cerebral infarction were prominent. Since the fifties, pathological, physiopathological and therapeutic studies have been one of the main flow of research in the Chair. Brief accounts of studies on hypertensive encephalopathy and vascular accidents of the spinal cord are given.

[The concept of cerebral lacunae from 1838 to the present]. / Le concept de lacune cérébrale de 1838 à nos jours.

The term lacunae was first used by Dechambre (1838) referring to small cavities developed during the process of resorption within cerebral softenings. Some years later, lacunae was applied by Durand-Fardel (1843) to small cavities located in the basal ganglia and hypothetically attributed to old, healed cerebral softenings. Durand-Fardel (1842, 1854) described "l'état criblé" as many round small holes ("criblures") always containing a patient blood vessel and located in the hemispheric white matter. He believed that "état criblé" was caused by mechanical compression of cerebral tissue related to the dilatation of the blood cerebral vessels during repetitive cerebral congestion. Chronic dementia or delirium were considered as the clinical counterpart of "état criblé". In the second half of the XIXth century, the few reports about lacunae were confusing due to the imprecise use of the terms "lacunae" and "état criblé". Furthermore, some authors described lacunae as sequelae of haemorrhage, others as old softenings or both. In the beginning of the XXth century, the masterly work of P. Marie (1901) established a clear distinction between the "foyers lacunaires de désintégration" and "état criblé" de Durand-Fardel or single perivascular dilatation of one of the lenticulo-striate arteries at its entrance into the lenticular nucleus or post-mortem charges (cerebral porosity, "état de fromage de gruyère"). He described lacunae as small cerebral softenings caused by occlusion of the blood vessels by a "local arteriosclerotic process". However, he also stated that some lacunae containing a patent blood vessel were due to a perivascular space dilatation destroying the adjacent brain parenchyma by a process of "destructive vaginalitis". Marie observed that lacunae were frequently clinically asymptomatic, but "that the hemiplegia of the old people was more often due to cerebral lacunae than to cerebral haemorrhage or softening". During the first half of the XXth century, all the papers devoted to cerebral lacunae were in accordance with the work of P. Marie, developing his own's contradictions. Many authors emphasized the "destructive vaginalitis way" and claimed that lacunae were dilatations of the perivascular spaces. Many other authors developed the "softening way" masterfully illustrated by Fisher who considered lacunae as small deep infarcts caused by a specific pathological process of lipohyalinosis due to arteriolar wall modification by hypertensive disease.(ABSTRACT TRUNCATED AT 400 WORDS)

[A century of stroke in the Dutch Journal of Medicine (1857-1956)]. / Honderd jaar beroerten in het Nederlands Tijdschrift voor Geneeskunde (1857-1956).

In the middle of the 19th century physicians performing autopsy could recognise cerebral softening through arterial occlusion, and distinguish it from intracerebral haemorrhage (apoplexy). During life diagnostic possibilities were limited, until the introduction of arteriography in 1927. A low blood pressure and embolism from the heart were considered possible causes of brain softening. After the turn of the century, when blood pressure could be measured, cerebral haemorrhage was generally attributed to arterial hypertension. The anatomical substrate of brain haemorrhage was controversial: bursting of a microaneurysm or a sclerotic artery, and primary infarction followed by increased permeability of vessel walls were all proposed as intermediate events. The subject of subarachnoid haemorrhage was first mentioned in the 1930s. Migraine and toxic factors were initially implicated as causes, later especially aneurysms. In the 19th century treatment of stroke would often involve blood-letting and application of dressings. Lumbar puncture was used in the 1920s and 30s for subarachnoid or intracerebral haemorrhages. In 1950 the first report about surgical occlusion of cerebral aneurysms appeared in the Journal.

Cases of stroke on the throne of Byzantium.

The authors describe the fatal illnesses of three Byzantine emperors, Alexander, Michael IX Palaeologus and Manuel II Palaeologus, who may have died of a stroke. From the texts of Byzantine historians and the indications of chroniclers, it was found that Alexander died of a stroke (possibly cerebral hemorrhage); Michael IX Palaeologus died of what seems to have been the same disease and the the last of these emperors, Manuel II Palaeologus, of hemiplegia. This paper provides the opportunity to see how the non-medical texts of historians and chroniclers adopt and express the scientific Byzantine terminology of the medical writers of the period, which is used differently today.

The alleged poisoning of Joseph Stalin: proof beyond reasonable doubt?

The name "Ioseb Besarionis dze Dzhugashvili" is as unassuming as it is unknown. It is the birth name of the brutal dictator who changed the face of Europe and whose actions still influence our lives today. Stalin, the man responsible for the slaughter of over twenty million of his own Soviet citizens and yet, the man who transformed the USSR from the feudalistic society of the Tsar's to a twentieth century military powerhouse that was instrumental in the defeat of Nazi Germany. Known as "Koba" to his friends, he cultivated a cult of personality where he was, and to a certain extent still is, admired in Russia and the former Soviet states. This paper will look at the following questions: why when he fell gravely ill did his comrades wait so long before seeking medical assistance? why were there omissions in the final post mortem report?, and why did one his closest lieutenants boast so openly about having murdered him.

[Roosevelt and Hopkins: a paretic president with a chronically ill adviser leading the United States during World War II]. / Roosevelt og Hopkins: en paretisk praesident med en kronisk syg rådgiver i spidsen for USA under 2. verdenskrig.

Succeeding Herbert Hoover in 1933 as President of the United States Franklin D. Roosevelt of The Democratic Party did not hesitate to make Congress immediately endorse his New Deal relief and recovery measures to help the depression-stricken Americans. Doing this, and during the rest of his life, Roosevelt had to cope with severe paralysis of his legs resulting from poliomyelitis infection in 1921 necessitating the use of leg braces and crutches, or a wheel chair. Before and during World War II Roosevelt leaned on Harry Hopkins, a former director of various health agencies with a penetrating mind and ability to discuss and implement Roosevelt's decisions. In spite of Hopkins suffering from the sequels of surgery for stomach cancer, he rendered invaluable support to the president. Franklin D. Roosevelt died 63 years old in April 1945 from a cerebral haemorrhage, and Harry Hopkins died 56 years old in 1946 from haemochromatosis.