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J Med Biogr OnlineFirst, published on March 21, 2014 as doi:10.1177/0967772013520101

Original Article

Virchow’s triad: Kussmaul, Quincke and von Recklinghausen

Journal of Medical Biography 0(0) 1–12 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0967772013520101 jmb.sagepub.com

John W Stanifer

Abstract For most of the 19th century, Germany was the centre of the medical world. From there the most innovating research came and many of the physicians of that era are known to nearly every medical student and physician of today. Virchow, Kussmaul, Quincke, von Recklinghausen, Mu¨ller and Scho¨nlein are familiar names in today’s medicine but insofar as they are merely eponyms associated with signs, symptoms, disease and anatomy. The story of their lives, their research and their influence on each other has been little examined. This is an essay about Virchow’s relationship with his mentors Mu¨ller and Scho¨nlein and how these relationships shaped the development of Kussmaul, Quincke and von Recklinghausen as students of Virchow and their work in medicine and clinical observation after leaving Virchow’s laboratory.

Keywords Virchow, eponym, triad, History 19th century, Cell Theory

Introduction In the history of medicine there are a few men who stand among the top pillars of influence, contribution and legacy. Rudolf Virchow (1821–1902) is one of those men. During his lifetime through most of the 19th century, German medicine was paramount and Professor Virchow was perhaps the most prominent physician, pathologist and researcher in the country. Today’s medicine that relies on an understanding of cellular biology and the fundamental mechanisms of health and disease can trace its beginnings to Virchow. His work led to the foundation of modern therapeutics and diagnostic medicine through his advances in pathology and the establishment of Cell Theory; it was through his work that knowledge of disease states fundamentally shifted toward viewing them not as imbalances of bodily fluids or outward mysterious influences but rather as abnormal physiologic processes, i.e. the field of pathophysiology or in the words of Virchow ‘pathologic physiology’. This alone would have been enough to establish his position in the annals of history; however, his influence as a teacher has further solidified his legacy. He taught many young physicians who went on to found schools, chair departments and contribute to scholarly research. The extraordinary milieu that Virchow created in his laboratory and clinics was one that fostered research as an important tool in patient care and, vice versa, bedside observation as an important spark for further

research. It was out of this environment that Kussmaul, Quincke and von Recklinghausen were moulded and because of which they would discover some of the most important clinical signs and syndromes in medicine; more so than any of his other students, these three names still find their way into the curriculum of medical schools and the wards of hospitals. In this sense, Virchow’s most lasting legacy may be his lesser known triad, his triad of students – Kussmaul, Quincke and von Recklinghausen.

Virchow’s early years Rudolf Virchow was born in Prussia in 1821 (Figure 1). Because of his family’s humble financial situation, in 1839 he enrolled as a medical student in the Friedrich–Wilhelms Institute in Berlin which offered free tuition. As it happens, Johannes Mu¨ller (1801– 1858), Europe’s most prominent anatomist, physiologist and microscopist, and Johann Scho¨nlein (1793– 1864), the famed clinician, were on Faculty there. The rise of German medicine and the generations of physicians who made that happen can trace their origins to Department of Medicine, Duke University Medical Center, Durham, NC, USA Corresponding author: John W Stanifer, Department of Medicine, Duke University Medical Center, Box 3182, Durham, NC 27710, USA. Email: [email protected]

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Mu¨ller and Scho¨nlein during their time in Berlin. Among Virchow and others, their students included Friedrich Jakob Henle (1809–1885) after whom the ‘Loop of Henle’ is named, Hermann von Helmholtz (1821–1894) who invented the ophthalmoscope and is considered the father of modern ophthalmology, Theodor Schwann (1810–1882) who conducted research on the nervous system, developed the early foundations of Cell Theory, and after whom Schwann Cells are named, and Ludwig Traube (1818– 1876) after whom Traube’s Space and Traube’s Sign are named. During Virchow’s time Mu¨ller was the Chair of anatomy, physiology and pathology (it was only after his death that the three departments were separated)1 and he is known to us today mostly through the eponym that carries his name, ‘Mu¨llerian agenesis’.2 He also confirmed the Bell–Magendie Law of neurophysiology which in summary states that the anterior spinal nerves carry only motor fibres while the posterior spinal nerves carry only sensory fibres. Scho¨nlein established his clinic in Berlin in 1840 and was a very wellknown clinician credited for bringing the diagnostic skills of auscultation and percussion to Germany.1 He is familiar to us today mostly through the disease that he described and which bears his name, Henoch–Scho¨nlein purpura and to a lesser extent through the ringworm he discovered, Trichophyton scho¨nleinii. For all practicality, the Friedrich–Wilhelms Institute was a military academy and the learning environment was a reflection of that. In an institute stifled with curricula that often were arcane, traditional and rarely based on evidence, Mu¨ller and Scho¨nlein were pushing the boundaries of this pedantic culture, as well as of medicine, by conducting exciting research in pathology, physiology, anatomy and clinical diagnosis. These two extraordinary professors were the exception rather than the rule, Mu¨ller with his exciting research in experimental physiology and microscopic anatomy and Scho¨nlein with his impressive clinical skills.3 On the one hand Virchow learned the scientific method, basic research and laboratory techniques from Mu¨ller and on the other he learned bedside manner, diagnostic skills and translational research from Scho¨nlein. It was in this dual mould that Virchow was trained and it would not only shape his medical career as one of the first true clinician–researchers but it would also shape him years later as a teacher himself. Within the first three years of graduation from medical school in 1843 Virchow would discover leukaemia and describe how thromboses and emboli form: he also coined the terms. He was the first to theorize that clots can form in vessels of one part of the body and then

travel to another as an embolus: Those plugs have been formed in any of the parts of the circulation before the lungs, in the veins or the right heart, and they have been carried into the pulmonary artery by the blood-stream.4

In a series of experiments to prove his theory, he took blood clots (thromboses) from human, horse and dog cadavers and inserted them into the proximal end of an incised jugular vein of live dogs. The clots were thus ‘deposited directly into the blood-stream of the subclavian and according to the theory it should then be found either in the right heart or in the pulmonary artery’. He found the clots always ended up in the pulmonary arteries and thus he had shown that the ‘venous blood-stream is able to carry away bodies with higher specific gravity than venous blood itself and to move them through the right heart into the pulmonary artery’.4 Further expanding on his new theory, in 1846 he published Further Investigations about the Obstruction of the Pulmonary Artery and Its Consequences in which he first described what would later be known as ‘Virchow’s Triad’. In his description of what we today call stasis or the first component of his famous triad he notes that

Figure 1. Virchow as a young man. Source: United States National Library of Medicine.

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Due to the insufficient contractility of veins, the remaining circulating blood cannot fill the whole lumen and maintain its former velocity. Therefore, over a certain distance inside the patent vessel a less rapid and possibly even stagnating blood-layer exists . . . [and] the slowing down of the blood stream is the main cause for spontaneous coagulation of the body veins . . . 5

However, he is quick to point out that this ‘stagnation of blood’ is not sufficient alone to produce thrombi and astutely he reworked concepts from Magendie’s and Paget’s6 experiments in prior years into his new theory about blood clots. He describes the second component of his triad, hypercoagulability or ‘an increase in the adhesiveness of the blood’, as such: Magendie’s experiments have sufficiently shown that any method to increase the adhesiveness of the blood — for example, one might admix oil . . . [and by] increasing the molecular attraction of the thus altered blood to the vessel-walls of the pulmonary capillaries [one can explain] an impairment of the otherwise easy passage of blood through the lungs.5

To Virchow, the role in inflammation or endothelial damage was less clear and he actually described it as a consequence of thrombus formation rather than as a precipitating factor. It was in fact Ludwig Aschoff (1866–1942), a student of von Recklinghausen, who cleared up the matter when in 1924 he showed that an ‘alteration of the vessel wall itself’ is an incendiary event in the development of thrombi.7 Nonetheless, by the age of 24 years Virchow had already described a new disease entity, leukaemia, as well as developed the doctrine of embolism effectively disestablishing the old model held guard by Carl von Rokitansky (1804–1878), Vincent Bochdalek (1801– 1883), James Paget (1814–1899) and Franc¸ois Magendie (1783–1855) among others. Incredibly his best years in terms of research, public policy and teaching were still ahead of him. It was Virchow’s political activism during the Revolution of 1848 that cost him his post in Berlin and subsequently resulted in his banishment to the University of Wu¨rzburg. He had begun to appreciate better than almost any other physician of his era the importance of public health projects in the form of sanitation, education and health care resources in promoting the general well-being, and he was quick to attack the government for its shortcomings. He declared that the government was ‘denying its people’s right to health’.3 Later that same year he became involved with the underground workings and back-currents of the revolution and began publishing pro-revolutionary pamphlets. He was even elected to the

Prussian Assembly as a Representative but eventually his liberal reforms and ideas cost him his job in Berlin.3 However, his liberal ideas fortunately led him to the home of Dr Karl Myer, a famous obstetrician, and in 1850 he married Dr Myer’s daughter Rosa. For their honeymoon they crossed the Swiss Alps and in his typical hard-working, inexorable fashion Virchow crossed most of the terrain on foot.8

Kussmaul’s development and career In Wu¨rzburg, Virchow was less of a threat to the political establishment but could still continue his work. Fortunately, his time there was no less prolific than his time in Berlin and by 1855 he had already begun to publish the early foundations of Cell Theory. In an essay published that year he formulated that his ‘aim was the foundation of a pathologic physiology . . . [through] the scientific method’ and articulated his famous aphorism omnis cellula e cellula (all cells arise from other cells).9 It was during this time in Wu¨rzburg that Adolf Kussmaul (1822–1902) came under his tutelage; he studied for two semesters in Wu¨rzburg with Virchow just when he was beginning to formulate the Cell Theory (Figure 2). Kussmaul had previously studied under Jacob Henle (1809–1885) and also under Franz Na¨egele (1778–1851) who today is remembered through his formula for calculating the expectant date in pregnancy known as Na¨egele’s Rule. Kussmual graduated from medical college in 1845 in Heidelberg and – like all serious students of the time – he went abroad after graduation to further his education and training. His first stop was Vienna in 1847 where Carl von

Figure 2. Professor Kussmaul assiduously working at his desk. Source: The Life and Times of Adolf Kussmaul.

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Rokitansky (1804–1878), Joseph Sˇkoda (1805–1881) and Ferdinand von Hebra (1816–1880) the ‘Father of Dermatology’ were making their ground-breaking discoveries. Every morning from seven to nine o’clock he attended Dr Hebra’s lectures on skin disorders which he found ‘most instructive’, but he spent most of his time either at Rokitansky’s afternoon autopsies that were performed after all deaths at the large twothousand bed hospital or at the clinics with Sˇkoda.10 From Vienna Kussmaul travelled to Prague and then was set to move onward to study in Berlin with Virchow who by that time in 1848 was gaining a reputation. However, the German revolution thwarted his efforts and he was side-tracked into a brief military career followed by private practice. It was not until 1853 when Virchow was exiled in Wu¨rzburg that he was able to undertake his studies with him; thus Kussmaul’s training, which had its beginnings in Vienna with Rokitansky and Sˇkoda, culminated with Virchow in Wu¨rzburg. Virchow’s influence upon Kussmaul as a clinician-researcher-pathologist is evident when comparing some of Kussmaul’s landmark papers. For instance, his 1866 description of Kussmaul-Maier Disease or periarteritis (polyarteritis) nodosa reads more like a textbook for pathologists and it is reminiscent of his time with Rokitansky in 1848, before Virchow, when they first noticed the disease entity. In Rokitansky’s case there was a description of a systematic disturbance of the arteries,11 and in Kussmaul’s later description of a 27 year old tailor’s journeyman whom he saw on 4 May 1865 in his Freiburg medical clinic and of a 28 year old day labourer he saw in August 1864, he takes a similar albeit more accurate approach. In describing the case he does give a short clinical history but the focus is on the pathology: [The patient’s] appearance was reminiscent of the chlorotic persons who succumb to rapidly progressive tuberculosis . . . From the beginning there was no doubt about the existence of a diffuse nephritis because of the blood and high protein content of the urine . . . in the next days, the feeling of numbness appeared in the left hand, and a paralysis of the long finger flexors of both arms and the muscles of the thenar eminences developed rapidly . . . On June 2nd, the patient was in a state of extreme weakness. He was scarcely able to speak, lay with persistent severe abdominal and muscles pains, opisthotonically stretched, whimpering, and begged the doctors not to leave him. Death occurred on June 3rd at 2 o’clock in the morning.12

After the poor patient’s excruciating he describes the pathology at autopsy:

death,

Peculiar mostly nodular thickening (periarteritis nodosa) of countless arteries [including] the coronary arteries [and the arteries] in the bowel, stomach, kidneys, spleen, heart and voluntary muscles . . . Diffuse necrotizing mucosal enteritis, hemorrhagic erosions of the stomach, diffuse nephritis [Bright’s Disease], bronchitis, and wide-spread granular degeneration of the voluntary muscles and the heart muscle.12

Compare this with Kussmaul’s later discoveries after his time with Virchow when he had cultivated the ability to be a clinician–researcher with a focus on ‘pathologic physiology’. The clinical picture Kussmaul painted in 1874 of ‘A Peculiar Type of Dyspnoea’: In this type of dyspnoea there is not the least suggestion as is so common in all other types that the passage of air to or from the lung has to combat obstruction in its path; to the contrary it passes in and out with the greatest of ease. The thorax expands noticeably in all directions without a pulling-in of the lower end of the sternum or intercostals spaces . . . and this complete inspiration is followed by a likewise complete expiration . . . Yet everything is indicative of extreme air hunger, such as the discomfort of angusty of which the patient complains, the extreme activity of the respiratory muscles, and the loud noise that the powerful inspirations and more so the expirations make . . . A true stridor, however, never exists . . . To the contrary the noise of expiration often becomes a groan even when the patient lies unconscious in deep coma . . . The marked contrast between the extreme general weakness of the patient and the powerful respiratory movements is a striking peculiarity of this picture.13

His account of an acidaemic, diabetic coma remains the most lucid and clear of any to this day and rightfully this type of dyspnoea is named after him as Kussmaul’s Respirations or Kussmaul’s Coma. Further, when he described pulsus paradoxus and Kussmaul’s Sign it was by correlating and combining his impressive observational and examination skills with pathology found at autopsy. In 1873 Kussmaul published a series of case reports in which he describes in detail ‘pulsus paradoxus’ – a term he coined – as well as define the sign that would later bear his name. In the case of a 21 year old farmer, Kussmaul first described what he found on physical examination. He noted a ‘fast heart rate [and a] pulse that was at first small and disappeared completely with inspiration and returned during expiration . . . This could be demonstrated also at the carotids as well as the radials; palpation of the femoral arteries was prevented by oedema’. He also noted tachypnoea and distended neck veins, especially the internal jugular,

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which became even more distended with each inspiration very markedly on the right and less conspicuously on the left. At the same time with each inspiration one to two retrograde waves were visible in a small subcutaneous vein that ran in the direction of the omohyoid muscle.14

At autopsy he found adhesive mediastinitis– pericarditis that had completely obliterated the pericardial space.14 In his next case of a 34 year old servant girl whom he diagnosed at autopsy as having chronic bronchitis, adhesive mediastinitis and chronic pericarditis, Kussmaul observed anasarca, dyspnoea, tachycardia and an ‘arterial pulse that would become smaller with inspiration or would become totally impalpable with deep inspiration [and which] on expiration returned to its former amplitude’. He further described the ‘supraclavicular fossa [as being filled] by the bulb of the internal jugular vein, [and] even the external jugular veins were very distended’. Interestingly, he also described the heart sounds as being clear but ‘very faint’.14 These observations are easily recognizable as the signs of cardiac tamponade physiology and one wonders if Kussmaul had had the advantage of Scipione RivaRocci’s (1863–1937) enhanced sphygmomanometer developed in the 1890s he could have described Beck’s Triad (lowered arterial blood pressure, distended neck veins and muffled heart sounds, all indicating cardiac tamponade) 60 years before Dr Claude Beck (1894– 1971)! It is noticeable that the focus had shifted from the pathology at autopsy to the clinical scenario that preceded it; he had learned, from the ‘foundation of pathologic physiology’ built by Virchow, how to give clinical significance to pathologic and microscopic discoveries. Because he was a prolific researcher, skilled pathologist and dedicated clinician with the ability to bridge pathology and physiology, he was able to discover these most lasting and eponymous contributions to medicine. His debt to Virchow was acknowledged by Kussmaul himself by dedicating his graduation thesis at Wu¨rzburg to him ‘for the many favours shown to me [Kussmaul] while he was in [there] from November 1853 to the end of August 1854’.10

Virchow and von Recklinghausen Virchow’s time in Wu¨rzburg was only temporary, however, and it was in fact Mu¨ller who was able to procure an academic post for him back in Berlin. He returned in 1856 as the new Chair of Pathology and leader of the new Institute of Pathology. From this institute, under Virchow’s wing, came nearly all of the professors of pathology in Germany over the next 50 years. It was from this Institute that he began, in the late 1850s, his

famous Twenty Lectures on Cellular Pathology which, in the words of William Sanders, ‘destroyed for all time the old humoral pathology and attracted to him the leading students and scholars of the world’.9 Virchow had effectively changed the course that medicine took for the next century by paving the way for molecular and cellular biology as well as modern therapeutics. Germany was undoubtedly the centre of the medical world and Professor Virchow stood right at the epicentre; Virchow’s influence reached beyond even the great physicians of Germany. He attracted American scholars including Dr William Welch (1850–1934) and Dr William Osler (1849–1919) who studied with him in the early-mid 1870s before returning to found Johns Hopkins Hospital. In 1900 Osler, in a speech at the Opening of the Museums of the Medical Graduates College at Johns Hopkins, would remark of the debt that he and all of American medicine owes to Virchow: The debt of the present generation to Germany can never be paid. Think of the scores who have found inspiration in our common master Virchow; and in the scientific study of disease the Fatherland is still in the van.15

It was during these early years of Virchow’s new Institute of Pathology that Friedrich Daniel von Recklinghausen (1833–1910) and Heinrich Irenaeus Quincke (1842–1922) developed relationships with the ‘great Master’, von Recklinghausen as the older and more experienced Post-Doctoral Assistant who had previously attended Virchow’s lectures in Wu¨rzburg and Quincke as a young undergraduate student. For nine years in the late 1850s and early 1860s von Recklinghausen studied and learned as one of the first assistants to Professor Virchow which in his words meant ‘he had made it’ (Figure 3).16 He learned new methods of staining and preparation techniques while in Virchow’s laboratory as evidenced by the publication in 1862 of his work in which he used a silver salt stain to demonstrate the communication between connective tissue spaces and lymphatic vessels. These minute lymph canaliculi would later be called von Recklinghausen’s canals.17,18 It was this work, while in Virchow’s laboratory, that led him to study the motion and identity of certain cells in these spaces that later he showed to be leukocytes and which added to the foundation for his and Julius Cohnheim’s (1839–1884) future studies of leukocyte migration and inflammation.19 After his departure from Virchow’s laboratory in 1864, von Recklinghausen accepted a professorship in Ko¨nigsberg at the impressive age of 31 before eventually being appointed Professor of General Pathology and Pathological Anatomy in Strasbourg in 1872

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Figure 3. Friedrich von Recklinghausen. Source: United States National Library of Medicine.

where he would remain until retirement in 1906.16 Over the next two decades von Recklinghausen established that inflammatory reactions develop not from in-situ metamorphosis of cells but rather from cells that have migrated from another ‘place of origin’. In the same way that Virchow had broken with the old establishment when he published his theory of embolization, von Recklinghausen broke with the old establishment that had regarded inflammation as a product of connective tissue cells that underwent marked changes and metamorphoses. He used an experimental model of corrosive keratitis by using a silver nitrate stick as the external stimulus. He then analysed the cells microscopically and noted ‘the cells were predominantly oblong, not circular, and many with protrusions, which were not static’. Using these protrusions ‘the cells were able to propel themselves forward using a pushing motion, and within half an hour the cells were able to traverse the observer’s field of vision’.20 It was this work that was also the basis for the concept of phagocytosis. He enjoyed great academic success in his life with the investigational skills he had learned from Virchow. He founded and co-edited the Archiv fu¨r Experimentelle Pathologie und Pharmakologie in much the same way that Virchow, in 1847, founded the Archiv

fu¨r Pathologische Anatomie und Physiologie und fu¨r Klinische Medizin21 and he served as Rector of the University in 1883. He was also known for his impressive lectures and laboratory teaching and among his students is Hans Chiari (1851–1916) who went on to describe the Arnold–Chiari Malformation and the Budd–Chiari Syndrome. His demonstrations in pathologic anatomy were held three times per week, and in his recount as a student of von Recklinghausen, WT Councilman (1854–1933) describes ‘the students, each with a microscope and a few reagents, seated at long tables along which the specimens were passed after the professor had explained them, and each student took pieces for study as they went along’.19 Also among his famed students is William Welch who is known as one of the ‘Big Four’ at Johns Hopkins and founded an American school of pathology and education, the influence of which is still felt in today’s academic medical systems. As an indication of von Recklinghausen’s continued respect and admiration for his former teacher, in 1882 on the 25th anniversary of Virchow’s founding of the Pathological Institute of Berlin he put together a Festchrift, a celebratory work honouring a person during his lifetime, entitled On Multiple Fibromas of the Skin and their Relationship to Multiple Neuromas. In contrast to his earlier work that had been purely microscopic with limited clinical usefulness, this detailed and exhaustive description of the disease gave it clinical applicability and it still reads as though it were a textbook for clinicians. Like Kussmaul’s later works, the focus is less on the autopsy and more on the clinical findings in correlation with pathology and physiology, and Virchow’s influence is evident. In the two cases, the one of a middle-aged 55 year old woman with a ‘great attraction to the male sex’ and the other of a 47 year old male day labourer, he presented the original description of the disease that would later bear his name, Neurofibromatosis type I: [She had] innumerable nodules, almost over the entire outer skin layer, for the most part on stalks, while others sat on broad bases and were mostly simple spheres in all possible sizes . . . all covered with completely intact, almost smooth skin . . . [on examination] of the peripheral nerve trunks, which were easily palpable, [he] was able, with complete certainty, to prove the existence of thickenings on the trunks in their gross distribution.22

He goes on to describe what modern textbooks regard as ‘cafe´-au-lait’ spots when on closer examination it was ‘revealed the existence in many places, particularly on the trunk and throat, of innumerable brown pigmentation spots . . . [and] there was a larger [4x3cm] pigmentation spot on the left buttocks . . . ’22

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Further, in 1889 von Recklinghausen coined the term ‘haemochromatosis’ to describe the disease entity that had been described originally by Armand Trousseau23 (1801–1867) in 1865. This required an ability to recognize not merely a pathologic process but also a clinical syndrome of diabetes mellitus, skin discolouration, and congestive heart failure. He reported on haemochromatosis: The pigment haemofuscin is characterized by its colour and very fine granular amorphous appearance, [and] it is found in the cells of smooth muscle, in blood and lymph vessels, lymph glands, in the liver, and in the pancreas . . . 24

Although it had been described by multiple individuals in the previous decades including Armand Trousseau, Victor Hanot (1844–1896), Charles Troiser (1844–1919) and Anatole Chauffard (1855–1932), it was von Recklinghausen who first recognized it as a disorder involving iron metabolism leading to iron deposition in the organs, and in the mould of Virchow, he linked that to the clinical phenotype of the syndrome. Instead of merely reporting pathologic facts, he again gives greater weight to his findings by making them clinically useful. Figure 4. Professor Heinrich Quincke. Source: United States National Library of Medicine.

Quincke’s success Quincke’s academic achievement was as precipitous and prolific as von Recklinghausen’s. After graduation from Berlin and Virchow in 1863, he was appointed Assistant Surgeon and then eventually Assistant Physician in Internal Medicine at the Charite´ Hospital in Berlin. A few years later, in 1872 at the impressive young age of 30, Quincke was called to Bern as Professor of Internal Medicine and again in 1877 he was called to Kiel as Professor and Chair (Figure 4).25 Quincke was the first to develop lumbar puncture for therapeutic purposes and then to realize the diagnostic implications of the procedure. In describing Quincke’s Triad, he used pathology results at autopsy to confirm that his clinical observations were consistent with the diagnosis and he did the same in describing Quincke’s Oedema and Quincke’s Sign. He was an Internist in the best sense of the word; he made significant discoveries in cardiology, gastroenterology, neurology, surgery, immunology and haematology, among others. In 1868, while Assistant Physician in Internal Medicine to Friedrich von Frerichs (1819–1885) who was Scho¨nlein’s successor and under Virchow’s guidance as Chair, he used his strong clinical skills to demonstrate that capillary and venous pulsations under the nail beds are useful in making the diagnosis of aortic

insufficiency. Today this is known as Quincke’s Sign or Pulse. While capillary pulsations can be seen under normal conditions, Quincke elaborated that A large and rapidly falling pulse is seen especially in aortic insufficiency, and for this reason the capillary pulse is especially clear in this condition . . . [This is best observed] in the area between the whitish, bloodpoor area and the red injected part of the capillary system of the nail-bed, [and] in the majority of persons examined, there is, with each heart beat, a forward and backward movement of the margin between the red and white part . . . [It is further noted] that the increase of the redness follows a moment later than the apex beat and is still clearly systolic and rather rapid, while the backward movement of the edge of the redness seems to take place more slowly.26

Quincke further and astutely observed that these capillary pulsations are also visible in the retina which today is known as Becker’s Sign. Although Becker’s Sign traditionally is associated with Graves-(Basedow) Disease, here, in the same 1868 paper, Quincke described both signs in a patient with aortic insufficiency.

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During this same time as an Assistant Physician in Berlin, he also described Quincke’s Triad which consists of epigastric pain, jaundice and upper or lower gastrointestinal bleeding used together to diagnosis haemobilia (bleeding into the biliary tree). In 1871 he presented the index case describing his triad in association with a ruptured intra-hepatic aneurysm causing haemobilia. The case was a 25-year-old day labourer who developed jaundice, abdominal pain and haematechezia (fresh bleeding from the rectum) following an episode of typhoid fever. At autopsy he noted . . . an aneurysm approximately the size and shape of a Lambert nut [hazelnut], surrounded by the liver parenchyma and located next to the main branch of the hepatic artery . . . It was located near the right hepatic duct which was displaced by it and enlarged as the other ducts . . . In that portion of the right lobe of the liver corresponding to the injured duct, soft, reddish brown areas were evident.27

After his appointment in Bern, Quincke’s research focused on expanding the previous observations of Johann Czermak (1828–1873) a decade earlier in the 1860s. In 1865 Czermak had studied the effects of carotid sinus stimulation on himself but Quincke expanded on the physiologic response. In 1875 he provided one of the earliest and clearest reports of the carotid sinus baroreflex and he even postulated that it was the vagus nerve lying next to the carotid and not the carotid itself that was responsible for the phenomenon:28 Through repeated and careful observations, a slowing of the pulse when pressure is applied on the carotid is a frequent finding in healthy as well as in sick persons.29

Although it was another 50 years before Heinrich Hering (1866–1948) characterized the detailed physiology responsible for the carotid sinus-mediated baroreflex and discovered the Sinus Nerve of Hering in the process,30 Czermak and more so Quincke nonetheless recognized the clinical importance of their findings. Indeed, the manoeuvre of carotid sinus massage still has significant clinical importance today. The origin of it can be traced back to Czermak and Quincke, and for that reason the manoeuvre of carotid sinus massage in an attempt to induce bradycardia should properly be referred to as the Czermak– Quincke Manoeuvre. In 1874 after his marriage to Berta Wrede who, as it happened, was the daughter of a wealthy family, he was able to support himself in academia without having a private medical practice on the side like most of the physicians of that time.31 He made productive use of his favourable arrangement and three years after his marriage, in 1877 he was called to Kiel

as a Professor and Chair. It was there that he would remain until retirement 31 years later. In 1882 he presented his case presentations of angioneurotic oedema or what would later be called Quincke’s oedema. Although his presentation is not the earliest recorded of angioneurotic oedema, it is the most thorough and clinically useful description and Virchow’s influence is manifest; like Kussmaul and von Recklinghausen, Quincke links clinical findings to underlying physiology in an effort to build a ‘pathologic physiology’ in the form of Virchow. In his 1882 paper, Acute Circumscribed Oedema of the Skin, he writes This disease appears as oedematous swelling of the skin and the subcutaneous tissue in localized lesions from 2 to 10 cm. or more in diameter. These swellings are most common on the buttocks and on the face, particularly on the lips and eyelids. The swollen parts of the skin are not always demarcated from the surrounding tissue which may be pale or translucent or reddened.32

Quincke further describes the overall clinical picture as well as detail why this oedema should be called angioneurotic rather than vasomotor, an important distinction not made by any of his predecessors: . . . pruritis is not common - localized swellings also appear in the gastrointestinal mucosa producing symptoms. In one case serous effusions in the joints were noted. In some, malaise, a slight headache, chills and oliguria appear. Because of its manner of development . . . it should be considered as an angioneurosis. It cannot be purely a vasomotor phenomenon, but is probably related to an alteration in the permeability of the vascular channels from a nervous influence.32

The first description of Quincke’s Oedema is detailed and vivid enough still to hold true for clinicians of today, and importantly he details a clinical picture that is not localized just to the skin. He notes that ‘gastrointestinal symptoms’ as well as ‘chills and oliguria’ occur: important facts that are easily overlooked. Quincke first presented his work on lumbar puncture, a new and controversial technique, at the Congress on Internal Medicine in Wiesbaden in 1891. His work on cerebrospinal fluid actually began many years earlier in the 1860s while at the Charite´ Hospital in Berlin under von Frerichs and Virchow. During that time, in the same way that Virchow had studied dogs and horses when developing his theory of embolization Quincke studied the fluid of dogs and rabbits by injecting the subarachnoid space with mercury sulphide and studying where the dye was found. In this way he learned early on that the cerebral and spinal

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cerebrospinal fluid spaces are continuous and this led him to perform lumbar punctures on animal and human corpses as early as 1872.33,34 Therefore, when Quincke’s experience with paediatric cases throughout the late 1880s presented him with the recurrent problem of idiopathic intracranial hypertension and hydrocephalus, the stage was set for a lucid, simple but revolutionary solution; he took Virchow’s ‘pathologic physiology’ one step further into modern medicine by incorporating treatment modalities based on the underlying pathology. In the first case he performed a ventricular puncture and in the second a lumbar puncture: therefore [He] punctured the subarachnoid sac at the level of the lumbar spine, by introducing a thin stitch cannula between the 3rd and 4th [lumbar] vertebral arches up to 2cm and removed a few cubic centimetres of water-clear cerebrospinal fluid drop by drop.35

He cured the child of headaches by relieving his hydrocephalus but it would be a few years later before the diagnostic potential of the lumbar puncture was realized. Again, Quincke was the pioneering investigator: he undertook a series of experiments to determine the specific gravity, albumin level, cell count, glucose levels and microorganisms in patients with tuberculous meningitis and bacterial meningitis.36 Nonetheless, physicians remained sceptical towards lumbar puncture and it was not until the turn of the 19th century that it became of widespread use. By that time Quincke had synthesized his data into a landmark publication in 1902 entitled The Technique of the Lumbar Puncture. He outlined in great detail not only the technique but he also described the central nervous system anatomy, the proper type of equipment to use, complications of lumbar puncture, determination of fluid content for diagnostic purposes and the therapeutic purposes of lumbar puncture in various diseases. He even mentions – to the chagrin of interns and students of today who often forget – ‘that the height of the [opening] pressure, which we should never neglect to ascertain when performing a lumbar puncture . . . ’ is of great diagnostic value.36

Later years In his later years Virchow continued his political activism as a member of the Prussian House and later the Reichstag, the German Parliament, in 1880. He remained an obstreperous voice and champion of the people, defending their rights at every turn; he was so relentless that he was challenged to a duel by Otto von Bismarck (1815–1898) for his harsh criticism of Bismarck’s questionable methods.1

Figure 5. Professor Virchow amid his anthropological collection that included many skulls and bones. Source: United States National Library of Medicine.

Virchow took a great interest in anthropology later in his career and he travelled far distances for his research. In 1879 he travelled to the Troas region of Turkey to study the archaeological artefacts of the City of Troy; he also happened to study the malaria outbreak occurring in that region in the same year. His personal collection of skulls, bones and various other archaeological artefacts matched that of most museums (Figure 5).1 The honours Virchow received in his life were prolific: in Berlin alone a street and a hospital were named after him. The celebration of his 80th birthday in 1901 brought delegates from around the Continent and correspondence from around the world. Sir Joseph Lister37 wrote from Britain that ‘he had learned from Professor Waldeyer of the celebration of Virchow’s 80th birthday’.38 In proper fashion with his voracious, almost transcendent workforce, Virchow ‘fell heavily on his left hip’ while jumping from an electric street car hurrying to an appointment on the morning of 1 January 1902. His diagnosis was described in almost textbook fashion; after being taken to his home, it was noted The limb was rotated outwards, was shortened by about 3 centimetres, and could not be manipulated without severe pain. The region over the trochanter and neck of the

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Journal of Medical Biography 0(0) femur was exquisitely tender; crepitus was obtained, the trochanter was displaced upwards and the range of movement was diminished. On this evidence, the diagnosis was made of fractura colli femoris intertrochanterica [fractured femoral neck].39

He never recovered fully from his illness and Professor Dr Rudolf Virchow died on 5 September aged 80 years after months of decline. On 9 September a civic public funeral was held at which medical celebrities, Ministers of State, State Officials and distinguished professors attended. At the funeral Professor Heinrich von Waldeyer40 (1836–1921) compared Virchow with Giovanni Morgagni (1682–1771) and Johannes Mu¨ller and counted up the researches and work that rendered his name immortal.41 In the later years of his career, Kussmaul continued to publish on motley subjects including gastric physiology, neurology, psychiatry and memory. In 1868 he was the first to use an oesophago-gastroscope and he visualized a carcinoma at the upper end of the oesophagus. He described dyslexia, calling it ‘word blindness’ in 1877 and in the same year he was the first to describe

Figure 6. Adolf Kussmaul lying on his death bed. Source: The Life and Times of Adolf Kussmaul.

Kussmaul’s Aphasia, selective mutism or as he described it ‘aphasia voluntaria’ in a 15-year-old child. In 1888 Kussmaul retired to Heidelberg and took the position of Professor Emeritus; however, his reputation had grown so much that patients continued to flock to him from across the German countryside. Unable to refuse his services, he continued to see patients until after the turn of the 19th century. In early 1902 on his eightieth birthday, exactly 20 years after von Recklinghausen had dedicated a Festchrift to their common mentor Virchow, volume 73 of ‘Virchow’s Archive’ was dedicated to him as a Festchrift. It contained 33 works that all directly or indirectly referenced Kussmaul’s abundance of researches. Just three months later, on the morning of 28 May 1902, Professor Dr Adolf Kussmaul died peacefully at his home (Figure 6).10 In 1906 von Recklinghausen became Professor Emeritus at Strasbourg but even in his retirement he continued to conduct research and to teach; he published his last significant work on bone pathology Untersuchungen uber Rachitis und Osteomalacie in 1910, the year of his death. He had been a ‘tireless worker, arriving at the laboratory at seven in the morning, and often remaining late into the night’19 and nearly all serious pathologists and physicians of the time had been influenced either by von Recklinghausen or by Virchow or by both. William Welch said of von Recklinghausen that like all great teachers ‘he had learned the first and last secret of teaching creativity in science – almost not to teach and never to force’.42 Professor Dr Freidrich von Recklinghausen died suddenly on 26 August 1910 at the age of 77. In his obituary he was described appropriately as ‘a man of fine personal character [and] as a teacher he had a great and deserved reputation’.43 Quincke’s interests later in his career focused on pulmonary medicine and surgery; he advocated surgical drainage of pulmonary abscesses and found that laying a patient with the feet elevated above the head (Quincke or Trendelenburg Position)44 helps with expectoration. His work in the field of pulmonary surgery merited him the only position as an Honorary Member of the German Association for Surgery awarded to a physician in internal medicine. Quincke went on to work on iron replacement therapy for iron deficiency anaemia, to coin the term ‘siderosis’ and to discover the causative agent of animal favus, known today as Trichophyton quinckeanum.25 He became Professor Emeritus in 1908 and then moved to Frankfurt where he continued to give lectures for another 14 years. In his retirement he was nominated eight times between 1909 and 1922 for the Nobel Prize in Medicine or Physiology for his work on introducing lumbar puncture, Quincke’s Oedema, iron metabolism and anaemia, and for his contributions to

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pulmonary surgery. Just a few months shy of his eightieth birthday on 18 May 1922 Professor Dr Heinrich Quincke died suddenly while sitting at his desk in his library. His obituary read simply Professor Quincke, who introduced lumbar puncture and gave his name to a form of oedema, has recently died in Frankfurt, at the age of 80.45

Epilogue Although the medical sciences have passed these men by in most regards, it is certain their works have formed the basis for modern diagnostics and therapeutics. The milieu created in Virchow’s laboratory and clinics was a unique combination of research ability, clinical acumen and skill, and intellectual capacity that allowed the development of three of the most important clinician-researchers in the history of medicine. Virchow represented the supreme combination of Mu¨ller’s experimental talent and Scho¨nlein’s clinical expertise that made him one of the first and most important clinician-scientists in medicine. It was this duality that propelled him to recognize the importance of a new ‘pathologic physiology’ and to which we owe the prolific discoveries of Kussmaul, Quincke and von Recklinghausen. References and notes 1. Sigerist H. The great doctors: A biographical history of medicine. Eden and Cedar Paul (transl). 3rd ed. New York: Dover Publications, 1971. 2. There is debate concerning the etymology of Mu¨ller’s Manoeuvre (reverse Valsalva manoeuvre). 3. Otis L. Mu¨ller’s lab. New York: Oxford University Press, 2007. 4. Virchow R. About the obstruction of the pulmonary arteries. Froriep’s Neue Notizen 1846: 794. 5. Virchow R. Further investigations about the obstruction of the pulmonary arteries and its consequences. Traubes Beitrage zur experimentellen Pathologie und Physiologie. 1846; 2; 21–31. 6. Francois Magendie (1783–1855) and Sir James Paget (1814–1899) performed a series of experiments in the 1830s and 1840s in which Magendie more or less concluded that the coagulability of the blood is proportional to its ability to circulate easily and Paget concluded that urea is responsible for the increased adhesiveness between the blood and the vessel wall. Although their conclusions were for the most part erroneous, their experimental models served as an important conceptual framework for thinking of coagulability and flow in determining the cause of pulmonary artery clots and served as an important beginning for Virchow to establish his Triad. 7. Aschoff L. Thrombosis. Lectures on Pathology. New York: Paul B. Hoeffner, Inc., 1924, pp.253–278.

8. Andree C. Letter of 24 Feb 1848. Der Briefwechsel mit den Eltern. Berlin: Blackwell Wissenchafts-Verlag, 2001, pp.317–318. 9. Sanders W. Rudolph Ludwig Karl Virchow: Pathologist, Anthropologist, Champion of German Liberty. Bios 1953; 24: 177–189. 10. Bast T. The Life and Times of Adolf Kussmaul. New York: Paul B Hoeffner, Inc, 1926. 11. von Rokitansky K. Ueber einige der wichtigsten Krankheiten der Arterien. Denkschriften der kaiserlichen Akademie der Wissenschaften 1852; 4: 1–72. 12. Kussmaul A and Maier R. On a previously undescribed peculiar arterial disease (Periarteritis nodosa), accompanied by Bright’s disease and rapidly progressive general muscle weakness. Deutsches Archiv fur klinische Medicin 1866; 1: 484–518. 13. Kussmaul A. Zur Lehre vom Diabetes mellitus. Deutsches Archiv fur klinische Medicin 1874; 14; 1–46. 14. Kussmaul A. ‘Uber schwielige Mediastino-Pericarditis und den paradoxen Puls (On adhesive mediastino-pericarditis and the paradoxic pulse).’ Berlin klinische Wochenscher 1873; 10: 433–435, 445–449, 461–464. 15. Osler W. An address on the importance of post-graduate study. British Medical Journal 1900; 2: 73–75. 16. Warkany J. Friedrich Daniel von Recklinghausen and his time. Advances in Neurology 1981; 29: 251–257. 17. Friedrich von Recklinghausen (1833–1910): German Pathologist. Journal of the American Medical Association 1968; 205: 640–641. 18. von Recklinghausen F. The lymph vessels and their significance in connective tissue. Berlin: A Hirschwald, 1862. 19. Councilman WT, Von Recklinghausen FD (1833–1910): Proceedings of the American Academy of Arts and Sciences 1918; 53: 872–875. 20. Heidland A, Klassen A, Sebekova K, et al. Beginning of modern concept of inflammation: the work for Friedrich Daniel von Recklinghausen and Julius Friedrich Cohnheim. Journal of Nephrology 2009; 22: 71–79. 21. Nicknamed and later formally named ‘Virchow’s Archive’, the Journal was personally edited by Virchow for over a half-century and is still in existence today as the official journal of the European Society of Pathology. 22. von Recklinghausen F. Ueber die multiplen Fibrome der Haut und ihre Bezienhung zu den multiplen Neuromen. Berlin: A Hirschwald, 1882. 23. Armand Trousseau (1801–1867) was a French Internist who is better known today for Trousseau’s Sign of Malignancy and Trousseau’s Sign of Latent Tetany. 24. Von Recklinghausen F. Haemochromatosis. Berlin klinische Wochenscher 1889; 26: 925. 25. Heinrich Irenaeus Quincke (1842–1922) Clinician of Kiel. Journal of the American Medical Association 1966; 196: 136–137. 26. Quincke H. Observations on capillary and venous pulse. Berlin klinische Wochenscher 1868; 5: 357–379. 27. Quincke H. A case of aneurysm of the hepatic artery. Berlin klinische Wochenscher 1871; 8: 349–352. 28. Adams A. Inhibition of the heart as an aid in diagnosis. The Transactions of the California Medical Society 1900; 30: 601.

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29. Quincke H. Vagus stimulation in man. Berlin klinische Wochenscher 1875; 12: 189–191. 30. Hering H. Die Aenderung des Herzschlagzahl durch Aenderung des arteriellen Blutdruckes erfolgt aus reflekteorischem Wege; gleichzeitig eine Mitteilung u¨ber die Funktion des Sinus caroticus, beziehungsweise der Sinusnerven. Pflu¨gers Archiv fu¨r die Gesamte Physiologie des Menschen und der Tiere 1924; 206: 721–723. 31. Go¨ring HD. In memory of the 160th birthday and the 80th anniversary of the death of Heinrich Irena¨us Quincke, as well as of his description of angioedema 120 years ago. Hautarzt 2002; 53: 822–825. 32. Quincke H. Acute circumscribed oedema of the skin. Montash fu¨r Praktik Dermatologie 1882; 1: 129–131. 33. Frederiks JAM and Koehler PJ. The first lumbar puncture. Journal of the History of the Neurosciences 1997; 6: 147–153. 34. Quincke H. Zur Physiologie der Cerebrospinal Flussigkeit. Archiv fu¨r Pathologische Anatomie und Physiologie und fu¨r Klinische Medizin 1872; 5: 153–177. 35. Quincke H. Ueber Hydrocephalus. Verhandlungen des X Kongresses fu¨r innere Medizin 1891; 10: 321–329. 36. Quincke H. The technique of the lumbar puncture. Berlin: Urban & Schwarzenberg, 1902. 37. Sir Joseph Lister (1827–1912), British Surgeon, is generally considered the first to develop and recognize the importance of anti-septic techniques using Carbolic Acid as the first anti-septic solution (‘Listerene’).

38. Lister J. Virchow’s eightieth birthday. British Medical Journal 1903; 2: 117. 39. Virchow’s last illness. British Medical Journal 1902; 2: 1454. 40. Heinrich Wilheim Waldeyer (1836–1921) was a German Anatomist and Histologist known today for his description of Waldeyer’s Tonsillar Ring, Waldeyer’s Gland (sweat glands of lower eye lid), and Waldeyer’s Sheath/ Space in the bladder wall. 41. Virchow’s Funeral. British Medical Journal 1902; 2: 807. 42. Fleming D. The creative tradition. William H. Welch and the rise of modern medicine. Boston, MA: Little Brown and Company, 1954, pp.32–41. 43. Professor von Recklinghausen’s Obituary. British Medical Journal 1910; 2: 84. 44. The Trendelenburg position was first described by a student of Friedrich Trendelenburg (1844–1924) in 1885 while Quincke’s first account of the position was not until 1898. Although today the position is generally referred to as the Trendenlenburg position, there are some slight differences in the two positions according to the original descriptions. The Trendenlenburg position has the patient on a 45 incline (head down) with the legs (bent at the knee) hanging off the edge of the bed and the Quincke position has the patient supine but simply raises the foot end of the bed such that the head and feet are on two separate but parallel planes. 45. Professor Quincke’s Obituary. British Medical Journal 1922; 2: 68.

Author biography John W Stanifer, MD, is a Resident Physician at Duke University Hospital in Durham, North Carolina, United States who currently is practising internal medicine and global health medicine. After obtaining a bachelor’s degree in philosophy, he studied for his medical doctorate at the University of Tennessee. In addition to his plans to pursue a career in academic Nephrology, Global Health and Internal Medicine, he has a strong interest in the history of medicine especially as it pertains to disease recognition and physical diagnosis. He hopes to build a career in which the scholastic study of medical history will provide enhanced and more effective patient care on a global and regional basis. He is a member of the American College of Physicians, The Southern Society for Clinical Investigation and Duke University School of Medicine Trent History of Medicine Society (Email: [email protected]).

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Virchow's triad: Kussmaul, Quincke and von Recklinghausen.

For most of the 19th century, Germany was the centre of the medical world. From there the most innovating research came and many of the physicians of ...
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