Apoplexy, cerebrovascular disease, and stroke: Historical evolution of terms and definitions

ABSTRACT. The long-standing concept of “apoplexy' can be followed from Antiquity, passing through the Middle Ages and Renaissance, and reaching the Modern era and the present day, with the new designation of “stroke”. The definition of “apoplexy” can be divided, by the history of autopsy, into a period predating this practice, which spanned from Antiquity until the Renaissance, with a relatively stable clinically-based umbrella concept, and an autopsy period of the Modern era, when the condition was subdivided into several subtypes. Thus, it took about 2,500 years assembling the numerous pieces of information to achieve a fairly well-defined picture. The “stroke” concept inherited the information developed for “apoplexy”, incorporating all historical acquisitions to form the current state of this knowledge.


INTRODUCTION
C erebrovascular disease refers to a group of disorders of the brain vasculature that may affect the blood supply of the underlying tissues. 1,2 This condition should be analyzed considering the pathology of the cerebral vessels (extra-and intracranial), as well as the resultant consequences on the brain parenchyma and related structures. The diseases of the vasculature include those of the large arteries (e.g., arteriosclerosis of cerebral arteries), of the small arteries, as well as of the venous vessels, besides cardiovascular conditions (e.g., emboligenic), and systemic illnesses. 3 The parenchymal lesions are var-ied, comprising ischemic changes, such as infarcts (large, small, lacunar, microinfarcts, watershed) and white matter ischemia (demyelination and axonal loss [white matter rarefaction], leukoencephalopathy), and hemorrhages (large lobar, basal ganglia, microbleeds, among others). 3 Cerebrovascular diseases can be asymptomatic or subclinical (silent or covert), or appear as an overtly expressed clinical manifestation in the form of "stroke" (cerebrovascular accident). 1,2 The term "stroke", which represents an acute event leading to clinical symptoms of neural dysfunction, 4 is regarded as having evolved from the ancient designa-tion "apoplexy", which likewise refers to a clinical concept characterized by rapid loss of consciousness, and various manifestations of brain dysfunction. The "apoplexy" concept used to embrace varied disorders, later identified as acute cerebral events, vascular and non-vascular (e.g., abscess, hydatids, pus, tumors, among others), as well as non-cerebral acute occurrences (e.g., myocardial infarction, pulmonary embolism, intoxications, among others). 5,6 The term "stroke" was introduced in the course of the historical studies and after a long time came to replace "apoplexy", a term which has virtually disappeared from the medical literature. 7 The historical highlights of the above-mentioned terms and concepts will be outlined, with a focus mainly on Western medicine, from Antiquity to the Modern era.

APOPLEXY: TERM AND CONCEPT
The term (apoplexia) ("struck down with violence", "to strike suddenly") has been used since Antiquity, identifying, in the ancient and clinical sense of the term, a disorder in which "a person suddenly falls, without consciousness or motion, retaining pulse and respiration". 5,6,8 This characteristic picture was well known to the ancient Greeks, at least 2,500 years ago, and "in all probability, long before, it was mentioned in writings that have not come down to us, and by authors whose names have been entirely forgotten". 9

ANTIQUITY: THE GRECO-ROMAN PERIOD
This period spans about 1,000 years (c. 500 BC-c. 500 AD), when the bases of the concept was established. Many authors contributed with their knowledge, and despite lost documents, a coherent narrative took shape. Some of the many authors will be named. 10 Hippocrates (and the Hippocratic Corpus) is responsible for the first recorded appearance of the term "apoplexy". The concept is mentioned in several parts of his extensive work, describing the clinical picture, with some variations 5,11 (Box 1).
The Hippocratic age was followed by numerous personalities, such as Celsus (c. 25 BC-c. 50 AD), Aretaeus (c. I century AD), Archigenes (c. I-II century AD), Galen (129 to c. 210 AD), Caelius Aurelianus (c. IV-V century AD), among many others. 10 Galen deserves a special mention. He acknowledged the current notions on the theme, which he developed with ideas somewhat divergent from those of Hippocratic authors, maintaining, however, the original core 12,13 (Box 1).
It is important to remind that, at the time, the "humoral theory" (humors, spirits), as well as "divine punishment", was plainly in vogue as a determining fac-tor of the ailment, a notion that would begin to be abandoned only in the 18 th century of the Modern era. 7,10,13

MIDDLE AGES OR MEDIEVAL ERA
The Medieval history of apoplexy, extending from the 5 th to the 14 th century, was represented by numerous prominent names. The authors of the early Middle Ages maintained the Hippocratic-Galenic ideas, with minor variations. The high Middle Ages included Byzantine, Persian, and Arabic authors, and in the high and late epoch the authors were from Western Europe, mainly Italy, France, and Germany. The entire period was influenced by ideas from Greco-Roman and Arabic works, but without the introduction of novel concepts. [16][17][18]

RENAISSANCE
The Renaissance, between the 14 th and 17 th century (in Europe), witnessed a renewed rise of interest in the ancient Greco-Roman ideas. At the time, translations of the ancient works were performed. The promotion of human dissection (autopsy) allowed society to use this for forensic, health and scientific purposes, and led to the emergence of new knowledge. The discoveries during the medical Renaissance paved the way for modern medicine. 19 During the Greco-Roman, Medieval and Renaissance periods the term "apoplexy" was maintained by all authors, along with its umbrella meaning. Important changes would come with the autopsy findings of the ensuing period. Box 1. Definition of "apoplexy" in the Greco-Roman era.
Hippocrates. "Apoplexy" definition (not explicit) (De Morbis II): "Suddenly a healthy person is seized with head pain, immediately the voice fails, he snores, and the mouth is open (gapes), and if someone calls or moves, he only groans, nothing with meaning, gives (releases) copious urine, and does not perceive. If the fever does not seizes (appears), he dies in seven days. Because it seizes (comes), the health is generally spared". 5 And: "Suddenly seized with pain to the head, immediately the voice fails, and he becomes incapacitated (powerless). Here, within seven days, unless the fever seizes, he dies. If the attack is strong". 11 "Apoplexy" definition (explicit) (Aphorisms II-42): "It is impossible to remove a strong attack of apoplexy, and not easy to remove a weak attack". 14 Galen. Definition (De loci affectis, Commentary on Hippocratic Aphorisms): "Apoplexy is an unconsciousness of the mind, with a privation of the senses and a palsy of the body." Also: "Apoplexy is a privation of sense and motion in all the nerves". And: "In apoplexy the whole body suddenly is deprived of sensation and motion, with only respiration remaining, and if it is prevented, the apoplexy is maximum and very severe". 12, 13 Engelhardt Apoplexy, CVD and stroke history

MODERN ERA
Many changes occurred from the 17 th century on with the advent of autopsies, and "apoplexy" began to lose its unitary (umbrella) meaning. 20 The non-vascular intracranial and the systemic conditions began to be separated, and only the vascular-related events retained the original designation. A classification started to emerge, based on cadaveric examination, dividing the condition into increasingly numerous subtypes, and laying the foundations of the study of the chapter of "cerebrovascular disease(s)". Some of the most cited authors of the period, 21,22 and their contributions to the theme, will be mentioned, without diminishing the influence of many others (Box 2). • Wepfer (1658) identified non-traumatic intracranial hemorrhage -"subarachnoid hemorrhage" and "cere-bral hemorrhage", as separate from other "apoplexy" types. 23 Wepfer split, for the first time, the unitary "apoplexy" definition, marking the start of studies on vascular diseases of the brain or "cerebrovascular disease(s)". • Cole (1689) first used the term "stroke" to denote "apoplexy" in English medical writing . 24 The term would be adopted much later. • Biumi (1765) described a case of a non-ruptured saccular "aneurysm" of the carotid artery. 25 • Morgagni (1761) distinguished a "sanguineous" [intracranial hemorrhage], a "serous" [non-hemorrhagic], and a "neither sanguineous nor serous" apoplexy. 26 • Blackall (1814) identified a ruptured "aneurysm" of the basilar artery in a case of "subarachnoid hemorrhage". 27 Box 2. "Apoplexy" in the Modern era (from 17 th century on): discovery of subtypes timeline -authors and excerpts.

STROKE AND ILCD/ICD: PRESENT-DAY TERMS AND DEFINITIONS
The term "apoplexy" was maintained as a medical term in the 4 th Revision of the International List of Causes of Death (ILCD-4) (1929). The term was abandoned from the 5 th Revision onwards (ILCD-5) (1938). 39 The term "stroke" (cerebrovascular) appeared first in the ICD-9 (1968). 39 The definition of the concept by the World Health Organization (WHO) appeared soon after (1971 and 1980), 4,39 and more recently, a new definition was proposed by the American Heart Association-American Stroke Association (AHA-ASA) (2013) 15 (Box 3).

WHO (World Health Organization)
• "Stroke" definition (1971): "A sudden onset of disturbance of focal bran function due to the blockage or rupture of blood vessels." 40 • "Stroke" definition (1980): "Rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin." 4 AHA-ASA (American Heart Association-American Stroke Association) (2013) 15 • Ischemic "stroke": "An episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction." • Intracerebral hemorrhagic "stroke": "Rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma." • Subarachnoid hemorrhagic "stroke": "Rapidly developing signs of neurological dysfunction and/or headache because of bleeding into the subarachnoid space, which is not caused by trauma." • "Stroke" (not otherwise specified): "An episode of acute neurological dysfunction presumed to be caused by ischemia or hemorrhage, persisting ≥ 24 hours or until death, but without sufficient evidence to be classified as one of the above."