Vesalius (Chapter 4) and William Harvey brought light into the study of human anatomy and physiology, medicine, neurology, and stroke during the sixteenth century. Before their contributions, Galenic writings, teachings, and proclamations had dominated medical practice for almost 1500 years. Galen was born in the Greek city of Pergamon in 130 CE. Galen introduced the principle that the sick could be properly treated only if physicians understood how the body works and how disease disturbs function [1]. To know the normal workings of the body, physician healers required a detailed knowledge of structure (human anatomy) and function (human physiology). Galen dissected mostly animals. His own proclamations and writings were not based on any scientific research. He was the major advocate of the humoral theory of disease. Illness was attributable to an imbalance of the four humors in the body: blood, phlegm, yellow bile, and black bile. Galen taught that blood was the dominant humor and he promoted the practice of bloodletting that held sway for centuries. The liver was the source of the blood. Blood was thought to be constantly manufactured in the liver’s ample spongy depths made from the digested food brought there from the intestines. Treatments for most ailments were therefore designed to restore the balance of these humors and were comprised of enemas, emetics, and bloodletting [2].

How to approach care of patients? Galen’s idea of humors, miasma, and natural influences affecting health and disease held sway for centuries. The methods of science – observation, hypothesis generation, experimentation, careful review of results, and then, revision of hypotheses and concepts – began to take hold in various academic centers in Europe and Asia during an age of enlightenment. Andreus Vesalius had shown how the study of human anatomy should be conducted (Chapter 4). William Harvey had shown how knowledge about human physiology should be approached (Chapter 5), and Thomas Willis had reinforced the need for a scientific approach to anatomy and experimentation as an important predecessor to caring for patients (Chapter 6). But it was Giovanni Battista Morgagni who put the final nail in the coffin of the Galenian approach to medicine. Morgagni emphasized examination of the body after death, to determine pathology, as a critical way of identifying disease and contributing importantly to knowledge. Anatomy, physiology, and pathology were the triad of disciplines that lead to the understanding of disease.

During the final years of the nineteenth century, clinicians and researchers became aware of the role that platelets played in blood clotting and bleeding. During the early 1880s in Turin, Italian physician, histologist, and researcher Giulio Bizzozero used comprehensive intravascular microscopy and in vitro flow chamber studies to identify the role of platelets in both hemostasis and thrombosis [1,2]. Sir William Osler in 1886 established that platelets contributed to human thrombotic disorders, discovering them in white thrombi in atheromatous aortic lesions and on diseased heart valves [1,3].

Charles Miller Fisher was born on December 5, 1913. Like his older sister and older brother and the five other siblings who followed, Miller (as he liked to be called) was delivered at home. His parents lived in a simple frame house in Waterloo, in the southern part of Ontario, Canada. When Miller was 11, his mother died during childbirth while giving birth to the tenth child, who also died. He was raised by his father and a succession of stepmothers. As a young boy, he was often referred to as “Doctor.” He was an average student in school, spending much of his time with sports and outdoor activities. During high school, a respected teacher criticized a report that he submitted, admonishing him that he could do much better. This criticism stimulated him, and during his last two years in high school, Miller “turned up the burners” and began to study more assiduously. He read avidly. By graduation he was recognized as “the scholar in the class.” He was awarded a scholarship to the University of Toronto in recognition of his performance during high school [1].

Ancient medical practitioners believed in the “doctrine of signatures,” which stated that natural objects that resembled parts of the body could cure diseases affecting those parts. The eyebright plant was used to cure eye diseases due to the similitude of its flowers to blue eyes. The famous Swiss physician Paracelsus was a proponent of this doctrine and stated, “Nature marks each growth, according to its curative benefit.” Herbs were believed to have particular “signatures” given by God for people to identify and use. Although this doctrine had no scientific basis, it led to the discovery of a drug widely used today [1].

At the midpoint of the twentieth century there were no organizations devoted solely to stroke, and no stroke-oriented journals. In 1954, the American Heart Association (AHA) sponsored a cerebrovascular disease meeting held in Princeton, New Jersey. The attendees at this first conference were mostly internists and cardiologists. A second conference was held in January 1957. The preface to the Second Conference on Cerebrovascular Diseases noted that “because of the massive size of the subject, certain facets were not fully covered in the first meeting. For this reason and, as research activity in cerebral vascular disease has intensified, it was deemed wise to make plans for a second conference” [1].

Advances in stroke prevention and improvement in the care and management of stroke patients can, in a large measure, be attributed to advances in knowledge about various medical conditions and their treatment. These stories of stroke could not be written without some attention to the medical risk factors and comorbidities prevalent in stroke patients. Many books would be needed to cover all the medical history. Some information is covered in Chapter 38 on epidemiology and stroke prevention. This chapter includes brief clips about the development of knowledge and ideas concerning major important medical conditions and their management.

In December 1895, German physicist Wilhelm Conrad Roentgen announced that a form of radiation that he dubbed X-rays could penetrate solid substances and produce an outline of their interior contents. The use of X-rays became widespread and greatly improved physician’s diagnostic capabilities; doctors could look at broken bones, lungs, the heart, or the intestines. However, X-rays were very limited in showing the brain. The skull was radio dense and the fluid surrounding the brain made it appear as a homogenous density without any structural details [1]. The first X-ray image of the brain reported at the end of the nineteenth century was fraudulent. It was an image of a cat’s intestine filled with a mercuric compound, radiographed in a brain-shaped pan. The famous American inventor Thomas Edison attempted to image the brain. His fame was such that reporters and the general public waited outside his laboratory for two weeks in anticipation of the good news. His efforts were unrewarding [2].

Clinical trials have played a key role in the transformation of stroke from a neglected, untreatable condition to a field where some of the most dramatic outcomes are achieved. The development of concepts in stroke clinical trials has largely occurred during the last six decades and is closely linked to development of clinical trial methodology and evidence-based medicine in general. Stroke trials sometimes played a pioneering role in this development.

Knowledge about thrombosis, the formation of clots, dates back to Virchow, who is discussed in Chapter 13. Perturbation of a vessel leads to release of a thrombokinase that catalyzes the transformation of a precursor protein prothrombin to thrombin. Thrombin, a clot-promoting protein, catalyzes the transformation of fibrinogen (another precursor protein) into fibrin. Fibrin provides the scaffolding that holds clots together. Clots are necessary for survival since they stem bleeding. Equally necessary are chemical reactions that dissolve clots. An “activator” converts plasminogen (another precursor protein) to plasmin, a powerful fibrin-dissolving, clot-dissolving enzyme. Tissue plasminogen activator (tPA) is the molecule in question. It has the special property of acting upon plasminogen only in the presence of fibrin, only where there is a clot. The process of breaking up clots is referred to as thrombolysis. Thrombolytic agents act by breaking up fibrin bridges within thrombi and, in doing so, allow blood to flow. The process is often referred to as fibrinolysis since fibrin is the main target. Fibrinolytic drugs degrade the fibrin network mesh of red erythrocyte-fibrin clots. The formation of thrombi in the body stimulates a natural fibrinolytic mechanism for thrombolysis. Plasmin is formed and its activity is concentrated at the sites of fibrin deposition. The ideal thrombolytic agent would adhere specifically to fibrin in clots and would not affect circulating fibrinogen. Lowering circulating fibrinogen levels excessively could promote bleeding.

Carotid artery occlusion and the occurrence of ocular and hemispheric signs became recognized during the latter years of the nineteenth century. Surgical ligations of the carotid artery were attempted during the twentieth century. A prevalent notion at the time was that intracranial vasospasm of small vessels precipitated by extracranial carotid disease caused the symptoms. For this reason, the most popular treatment for carotid disease was sympathectomy. C. M. Fisher first suggested that “bypassing” the occluded carotid artery segment could preclude clinical manifestations. His contributions were a quantum leap in understanding the mechanisms of carotid stroke. More than half a century after his landmark publication, treatment of carotid artery stenosis is still debated.

Although the artery was successfully ligated, the patient died a week later; inflammation and sepsis caused the wound to swell, choking the patient. Cooper improved his technique and made yet another attempt to ligate a carotid artery three years later. He succeeded this time, and the patient lived for the next 13 years [3].

During the second half of the twentieth century and first quarter of the twenty-first, new cerebrovascular syndromes were identified. The advent of modern brain and vascular imaging allowed identification of previously unrecognized or underrecognized conditions. Once the diagnosis could be made clinically, further experience allowed recognition of the frequency, demography, clinical findings, and course of the conditions and paved the way for treatment. Four representative entities have been chosen that illustrate discovery and evolution during this time.

During the second half of the nineteenth century and early years of the twentieth century, clinicians described instances of focal brainstem lesions at various levels. The intent was to learn the location and function of various nuclei and tracts. Some lesions were due to infarcts and hemorrhages. Others were caused by tumors, infections, or other nonvascular processes. These focal lesions were usually named after the first describers. Herein are notable examples.