HISTORICAL VIGNETTE J Neurosurg 122:453–463, 2015 Fixed and dilated: the history of a classic pupil abnormality Peter J. Koehler, MD, PhD,1 and Eelco F. M. Wijdicks, MD, PhD2 1Department of Neurology, Atrium Medical Centre, Heerlen, The Netherlands; and 2Division of Critical Care Neurology, Mayo Clinic, Rochester, Minnesota The aim of this study was to investigate the development of ideas about the nature and mechanism of the fixed dilated pupil, paying particular attention to experimental conditions and clinical observations in the 19th century. Starting from Kocher’s standard review in 1901, the authors studied German, English, and French texts for historical information. Medical and neurological textbooks from the 19th and 20th centuries were reviewed to investigate when and how this in- formation percolated through neurological and neurosurgical practices. Cooper experimented with intracranial pressure (ICP) in a dog in the 1830s, but did not mention the pupils. He described dilated pupils in clinical cases without referring to the effect of light. Bright demonstrated to have some knowledge of the pupil sign (clinical observations). Realizing the unreliability of the pupil sign, Hutchinson in 1867–1868 tried to reason in which cases trepanation would be advisable. Von Leyden’s 1866 animal experiments, in which he increased CSF volume by injecting protein solutions intracranially, was the first observation in which the association between fixed dilated pupils and increased ICP was established. Along with bradycardia and motor and respiratory effects, he noticed wide pupils were usually present in a comatose state. Asymmetrical dilation could not always be attributed to increased ICP, but to an oculomotor nerve lesion. Pagenstecher in 1871 extended knowledge by meticulously studying consecutive pupil phenomena with increasing pressure. In 1880, von Bergmann emphasized the significance of the ipsilateral dilation in experiments as well as in clinical cases. He distinguished the extent of pressure increase and its duration. Probably confusing irritation (epileptic head turning to the other side with pupil dilation) and lesion effects, he suggested a cortical area responsible for oculomotor phenomena, indicating what is now known as the frontal eye field. Naunyn and Schreiber (1881) understood the relationship between increased ICP with pupil dilation and decreased pulse frequency and blood pressure, warning not to decrease the lat- ter. Concentrating on experimental traumatic effects, Duret (1878) investigated compression and commotion, in which he distinguished two phases, notably pupil constriction by bulbar lesions, due to CSF shock, followed by dilation from congestion and inflammation, due to blood around the oculomotor nerve. The key observation of a fixed dilated pupil as a sign of acute mass effect came gradually and after some localization stumbles. Following the period of extensive experimental research in ICP, the results of which were translated to clinical observations, the prognostic significance was gradually acknowledged by authors of neurological textbooks. It is well known that Cushing did similar experiments in Berne (1900–1901), and later suggested he would not have done so if he had studied the literature. http://thejns.org/doi/abs/10.3171/2014.10.JNS14148 KEY WORDS history of medicine; pupil; dilated; clinical; experimental; coma; intracranial pressure LIGHT-FIXED and dilated pupil is considered an At some point in time, laboratory observations translated iconic sign in acute neurology and neurosurgery, to clinical practice, but authors already often combined and has been considered a grave sign. Its signifi- laboratory study results with clinical case observations. Acance was not known before the 19th century. Although One of the first clinical articles was by surgeons Hol- changes in pupils in moribund patients have been known man and Scott, who emphasized that surgery should be since antiquity, laboratory studies that focused on mea- on the side of the dilated pupil.25 Pupil dilation became surements of the consequences of acute mass effect in the recognized in the deteriorating patient often coinciding brain provided the first pieces of information that led to a with decorticate or decerebrate responses indicating acute better understanding of its pathophysiological meaning. brainstem injury. Currently the pathophysiology is poorly ABBREVIATION ICP = intracranial pressure. SUBMITTED January 20, 2014. ACCEPTED October 2, 2014. INCLUDE WHEN CITING Published online November 21, 2014; DOI: 10.3171/2014.10.JNS14148. DISCLOSURE The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. ©AANS, 2015 J Neurosurg Volume 122 • February 2015 453 Unauthenticated | Downloaded 09/26/21 12:22 AM UTC P. J. Koehler and E. F. M. Wijdicks understood and speculatively explained, and the notori- ous pupil sign (fixed and dilated) is not as robust prognos- tically as was initially assumed. In a previous paper in which we studied the historical aspects of coma, we only superficially touched upon the aspect of the fixed dilated pupil.33 In the present study, we investigate the history of ideas about the fixed dilated pu- pil, in which we shall pay particular attention to the 19th century. Clinical observations as well as experimental conditions are presented. Literature Review Our starting point was Kocher’s standard review in 1901 that contains a wealth of references on traumatic brain injury (clinical as well as experimental) and spon- taneous mass lesions (in translation: “Brain concussion, brain pressure and surgical procedures in brain diseas- es”).32 Working from the references found in this review, we noticed a sufficient coverage of the topic in German, English, and French texts, although some of the references directed our attention to additional publications that were also consulted. We chose to describe the studies per coun- try (combining the German-speaking countries) rather than chronologically, although cross-references between some publications were found. We translated French and German quotations into English where applicable. We did not include Cushing’s work with Kocher and Kronecker in 1901–1902 in Berne, because this research was conducted in the early 20th century and has been described several times elsewhere.2,19 Moreover, Cushing was more interest- ed in circulation, intracranial pressure (ICP), respiration, FIG. 1. Ernst von Leyden (1832–1910). pulse, and blood pressure than in pupil changes.32 Medical and neurological textbooks from the 19th and 20th centuries were studied to determine when and how narcosis, he increased CSF volume by injecting protein this information percolated through neurological and neu- solutions up to a pressure of 180–900 mm Hg. Blood pres- rosurgical practices. We selected a representative list of sure was not measured, even though the German physiolo- books in English, French, and German from two standard 37 gist Carl Ludwig (1816–1895) was already working with books, notably Garrison’s History of Neurology and invasive procedures using his kymograph that he invented the “Diseases of the nervous system” section in Morton’s 41 in the 1840s. Von Leyden observed a diminution of the Medical Bibliography, and consulted several other stan- pulse frequency that could be prevented by sectioning of dard texts. the vagus nerves. When the pressure was decreased again, functions returned. Von Leyden summarized the changes Early German Experimental Studies he found in increased ICP, which we list in Table 1. Von Leyden was probably the first investigator to observe dilat- The work of a number of prominent German clinicians ed pupils by experimentally raising ICP.35 Equally impor- in the 19th century is presented here. They were aware of tant, he also noted that the cornea became insensitive to each other’s experiments and often refuted or confirmed touch.35 With increasing pressure the pupils first became observations. narrow, followed by dilation. He noticed that the dilation was not always symmetric, and it was the only pressure Von Leyden’s Experiments (1866) symptom that showed a difference between both sides. In In his authoritative book on cerebral trauma and ex- experiment no. VII, for instance, he mentioned that the perimental coma,32 the Swiss surgeon Theodor Kocher pupil on the left was dilated maximally, and on the right (1841–1917) mentioned Ernst von Leyden’s (1832–1910; constricted. He explained this by supposing that, “it is Fig. 1) 1866 paper on the physiology and pathology of the not impossible that the distribution of the pressure within brain among the key references with respect to the study the skull does not occur equally.”35 He realized that “the of ICP. 35 Von Leyden, at the time working in Königsberg symptoms of the visional system discussed here belong to (later a professor in Strasburg and Berlin), was particu- the most important diagnostics for the brain. Enlargement larly interested in “brain pressure and brain movements,” of the pupils should be considered a sign of considerably which was the subtitle of the paper. In his famous experi- increased brain pressure.”35 He deduced that asymmetri- ments on pathological cerebral pressure under morphine cal dilation could not always be attributed to increased 454 J Neurosurg Volume 122 • February 2015 Unauthenticated | Downloaded 09/26/21 12:22 AM UTC TABLE 1. Summary of von Leyden’s experimental findings in increased ICP* Finding