**2. Early understanding of stroke**

The word "apoplexy" was first documented in the Hippocratic Corpus and refers to a person collapsing while retaining pulse and respiration [21]. In Greek language the word αποπληξία (apoplixia) means to be struck with violence. The following extract from the Hippocratic writings gives a description of apoplexy: "The healthy subject is taken with a sudden pain; he immediately loses his speech and rattles in his throat. His mouth gapes and if one calls him or stirs him he only groans but understands nothing. He urinates copiously without being aware of it. If fever does not supervene, he succumbs in seven days, but if it does he usually recovers." [22]. In the Greco-Roman period apoplexy was a term used to describe strokes, epilepsy and migraines [21, 23]. The four humours (blood, phlegm, yellow bile and black bile) were first mentioned in the Hippocratic treatise called *The Nature of Man*, and it was actually the work of Polybus, Hippocrates' student [24]. According to Hippocrates, apoplexy was secondary to heating of the head blood vessels that brought phlegm or caused the flow of black bile to the head [22]. Aretaeus was the first to document the concept that apoplexy to one side of the brain results to the contralateral paralysis of the body [25]. Galen claimed that stroke was the result of humors imbalance resulting in blocking the transmission of the animal spirit [26]. Specifically, Galen believed that blood accumulated in the brain whereas phlegm and black bile accumulated in the cerebral ventricles [26].

During the Medieval era the concepts around apoplexy remained grossly unchanged [21]. The ideas of apoplexy in the Medieval era remained influenced by ideas from Greco-Roman works [21].

More information into the cause of apoplexy was obtained during the Renaissance era, between the 14th and 17th century [21]. During the Renaissance era autopsies were permitted and the ancient works were translated in this way expanding the knowledge of apoplexy [21]. In 1599, the Oxford English Dictionary gave a synonym for the "stroke of the palsy" as the "stroke of God's hands" [27].

From the 17th century and onwards the various conditions that made up the term apoplexy started to be individually explored [21]. In 1658, Johan Jakob Wepfer published "*Historiae apoplecticorum*" which was the first time that apoplexy was related to intracerebral hemorrhage [28]. Wepfer performed an autopsy on a patient who suffered from "apoplexy" and found that the brain and the ventricles

were filled with blood and no signs of external trauma were evident [28]. In 1689, William Cole was the first to use the term stroke to refer to apoplexy [21]. Others such as Morgagni (1761), Biumi (1765), Blackall (1814), Rochoux (1814) and Rostan (1819) shed light into diseases ranging from unruptured to ruptured aneurysms, as well as the difference between ischemic and hemorrhagic stroke [21].

### **3. The development of carotid endarterectomy**

In 1852, Rudloph Virchow played an important role in shaping our understanding of stroke as he was the first to identify that stroke was the result of an embolism and/or thrombus [21, 29]. In fact Virchow was the first to use the term "thrombosis" and "embolus" that can lead to decrease blood flow in distal vessels and can result in stroke [30].

Approximately 8% of all ischemic strokes are due to extracranial internal carotid artery stenosis [31]. Chiari in 1906 and Hunt in 1914 performed autopsies in patients who had suffered from cerebral infarction and noted that lesions in the cervical carotid artery could be the culprit for the stroke [32]. Fisher in 1951, published case reports that showed that the cause of cerebral infarction was secondary to occlusion of internal carotid artery [32]. The introduction of cerebral angiography in 1927 by Moniz played a crucial role in the understanding of carotid artery disease and the subsequent development of carotid endarterectomy (CEA) [33]. The first carotid artery reconstruction was completed in 1951 in Buenos Aires and it was the result of the combined work of Fisher, Murphy, Carrea and Mollins [34]. In 1953, Debakey successfully completed the first CEA surgery for a patient with cerebrovascular insufficiency [35]. However, Debakey did not publish this case report until 1975 [36]. In the meanwhile, in 1956 Cooley was the first to publish a case report on a patient undergoing a successful CEA [37]. This was also the first report of the application of a temporary shunt during a CEA [37].

In 1969, the Joint Study of Extracranial Arterial Occlusion was published that showed that in 2,400 operations performed between 1961 and 1968 there was a 4.5% surgical mortality [38]. The indications for CEA remained unclear and given the surgical risk associated with the surgery, it took years before it became the standard of care [39]. In 1991, The North American Symptomatic Carotid Endarterectomy trial (NASCET) and the European Carotid Surgery (ECS) trial proved that patients with symptomatic carotid stenosis of 70–99% who underwent CEA had better outcomes when compared to patients who were treated medically [40, 41]. Specifically, the NASCET study showed that there was an absolute risk reduction of 17 ± 3.5 percent (P < 0.001) of having any ipsilateral stroke at two years and an absolute risk reduction of 10.6 ± 2.6 percent (P < 0.001) for a major or fatal ipsilateral stoke when comparing patients who underwent CEA versus those who underwent medical management [42]. The ECS trial showed that patients with carotid artery stenosis of 70–99% (P < 0.0001) had a six fold reduction in their risk of experiencing stroke during the next three years if they underwent surgical treatment versus medical management [43].

In addition, in 1995 the Asymptomatic Carotid Artery Stenosis (ACAS) trial showed that patient with asymptomatic carotid artery stenosis of 60% or greater benefited from CEA [44]. In this study there was a 53% risk reduction of having a stroke in patients treated surgically versus those treated medically [44].

Subsequently there was also interest as to whether carotid artery stenting (CAS) could replace CEAs. In 2010, a randomized controlled trial showed that CAS was associated with a significant higher periprocedural risk of stroke, whereas CEA was associated with a higher risk of myocardial infarction [45]. This study also showed

that in the four year follow up there was no significant difference of further strokes between the two groups [45].
