Fixed and Dilated: the History of a Classic Pupil Abnormality

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 information 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 latter. 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 pupil, 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 diseases”).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 country (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 interested 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 History of the fixed and dilated pupil

dimi-

delirium,

headache

Analogy in Humans nution of intelligence sign for increased pressure meningitis due to fluc- tuations including Most important diagnostic In contrast to humans

More variability in humans, Pulsating

fluctua-

Observations

pulse

limbs

hind then possibly local by affection of third cranial nerve pain in deep coma tions intracranial by arterial compression in dia- stole Additional Opisthotonus; stretching of Not always symmetrical & Cornea insensitive to touch/ Increasing Notes respiration

narcosis

paresis

creased pressure in case of artificial times nystagmus-like movements phine nerve transection Animal would not die in- by After cramps, in coma; some- No Depending on the depth of mor- Observation limited morphine by No decrease in case of vagus skull†

pressure

Conclusion incontinence

sometimes anoxia pressure creased Vomiting rare, defecation Cardiac arrest because of Asymmetrical due to unequal Headache as symptom of in- No Diminution to complete coma 53 Cause affection

nerve of respiratory centre” loss of function) Sometimes local by third Death due to “paralysis Dura mater compression excitationVagus then (& >50 >120 >130 >130 >70–90 Increasing ICP Hg) (mm frequency

pulse enlargement

Finding pupil

increasing) to very irregular, to long ap- neas Digestive tract Cramps Senses, Circulation, decreasing then (& TABLE 1. Summary 1. TABLE of von Leyden’s experimental findings in increased ICP* Pain * Leyden Von mentions meningitis and brain tumor as examples of human conditions in which ICP is increased. He added that it is not always clear whetheraffections, symptoms are due as to in general the case action of asymmetrical of increased pupillary ICP or to local enlargement. † Leyden Von wondered whether this would be the explanation of unilateral dilation. Urinary tract Respiration: irregular, to deep, Change in consciousness

J Neurosurg Volume 122 • February 2015 455

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC P. J. Koehler and E. F. M. Wijdicks

ICP, but rather to an oculomotor nerve lesion. In the dis- Among the cases, we recognize an epidural hematoma cussion he also added that the phenomenon was usually with ipsilateral pupil dilation and contralateral paresis associated with coma. cured by trepanation. Partial oculomotor nerve lesions are mentioned ipsilaterally as well as contralaterally. He ex- Pagenstecher’s Experiments (1871) plained the latter from a probable central cortical cause, but only if it was a small lesion, and reasoned that in more In his Experimente und Studien über Gehirndruck profound hemisphere contusions it would have another published in 1871, Friedrich Pagenstecher, a surgeon in explanation. Interestingly, he applied the recent cortical Heidelberg, criticized von Leyden by stating: “About the localization theory to explain certain types of oculomotor pupil phenomena in brain pressure, we learn very little 44 lesions. Referring to Charcot, Pitres, Ferrier, Hitzig, and from Leyden’s studies.” Pagenstecher referred to the several others, von Bergmann suggested that the frontal clinical description of Jonathan Hutchinson (1867–1868, eye field not only served conjugated gaze reactions (Fig. see below). From his experiments, Pagenstecher con- 3): “Approximately at 1 the areas are situated from which cluded that pupil phenomena were not observed in cases the oculomotor will be affected (elevation of the upper without greatly increased brain pressure. Along with the lids, movement of the ball, dilation of the pupils, turning other symptoms that become more severe, the following 44 of the head to the contralateral side).” Most probably, he pupil symptoms were observed: 1) moderate constriction was confused between the general effects of epileptic phe- of the pupil on the operated side, only of short duration; 2) nomena (including sympathetic widening of the eyes and equal constriction of both pupils, usually of short duration pupil dilation) by local irritation and the effects of oculo- and once for 5 hours; 3) dilation of the pupil on the oper- motor nerve lesions. He demonstrated the suggestion with ated side up to almost disappearance of the iris; and 4) a clinical case including postmortem findings of frontal equal dilation of both pupils up to the maximum. Symp- lobe lesions.53 In another case, von Bergmann was con- toms 2–4 were always accompanied by sopor and coma. fused about the localization of an oculomotor lesion in a During convulsions, symptom 4 was always present. The case of traumatic basilar meningitis, supposing that usu- wide pupil was always fixed to light. Pagenstecher could ally cranial nerves are resistant against loss of function.53 not explain the early pupil constriction, which remained unexplained (Fig. 2). Naunyn, Schreiber, and Falkenheim’s Experiments Working in Königsberg (in Prussia), where von Ley- Von Bergmann’s Experiments and Clinical Cases den had performed his experiments about 15 years previ- The German surgeon Ernst von Bergmann (1836–1907) ously, Bernard Naunyn (1839–1925) and Julius Schreiber provided additional information in his large tome on head (1848–1932) in 1881 published their experiments in 170 injuries.53 He mentioned fixed dilated pupils in cerebral pages, of which more than 50 comprise pressure curves trauma as well as in experiments. One of the methods he and another 50 comprise tables, describing intracerebral applied to increase the pressure was described as follows:53 and carotid pressure as well as pulse and respiration.40 ... we observed that blood injected into the carotid with a They concluded that with increased ICP, blood pressure pressure of 500 mm was able to flow into the skull cavity should not be decreased (as by bleeding, see below); on the freely, as was shown by the simultaneous increase of the flow contrary, it should be increased. They mentioned pupillary velocity in the veins. In contrast, I obtained, in other cases, in dilation and referred to von Leyden and Pagenstecher, but which I put defibrinized blood in both carotids of a dog under also to Henri Duret’s work. Naunyn and Schreiber oper- 800 to 1000 mm, during the injection, stetorous breathing, ated on dogs (under narcosis, using curare and artificial decelaration of the pulse and pupillary dilatation. respiration!),40 and used von Leyden’s method to increase Von Bergmann often correlated the results from the the pressure. They did not notice differences between the experiments with clinical observations. He noticed differ- pupils. Pupil dilation did not always immediately follow ences between the left and right pupil in a way that the after increasing ICP. Sometimes pupil dilation was associ- ipsilateral pupil became narrower at first and then, with ated with increased blood pressure. In 1 experiment they increased pressure leading to coma, wider than the con- repeatedly noticed the association of increased ICP with tralateral pupil. He compared it with clinical situations, bradycardia, increased blood pressure, and pupillary dila- writing about “a patient whom I trepanned for a subdu- tion, as well as the other way round (if ICP was decreased, ral abscess, and in which this symptom only pointed to a bradycardia disappeared, blood pressure returned to nor- localized disorder. In a similar way, Hutchinson ... found mal, and pupils became normal).40 Interestingly, they pupillary dilatation on the side at which autopsy dem- concluded that the m. dilatator pupillae (the muscle that onstrated a hemorrhage between dura and bone.”53 He dilates the pupil) innervating nerve fibers originated in the also emphasized its duration, i.e., short duration with all medulla oblongata, “thus, from the same part of the cen- “pressure symptoms” may be reversible. With respect to tral nervous system that plays a main role in the vasomotor prognosis, he stated that, “only deep coma with absolute innervation” and that “excitation of the medulla oblongata muscle paralysis and insensibility for all stimuli, with pu- leads simultaneously to contraction of the vessels, i.e. in- pillary dilation and irregular deep respiration, almost al- crease of the blood pressure as well as constriction of the ways results in death.”53 pupil dilator and the other way round.”40 With respect to human cases, he provided several case Six years later in 1887, Bernard Naunyn published a descriptions (including those from colleagues and from new paper, this time in cooperation with Hugo Falken- the medical literature) and the effects of trepanation.53 heim (1856–1945).16 In addition to von Leyden’s and von

456 J Neurosurg Volume 122 • February 2015

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC History of the fixed and dilated pupil

FIG. 2. “Tafel I” (Plate I) containing 9 figures from Pagenstecher’s paper (Pagenstecher F: Experimente und Studien über Gehirn- druck. Heidelberg: Winter, 1871). Coronal sections of partly hardened (on ice) brain representing studies in which a mixture of wax and tallow was injected epidurally.

Bergmann’s experiments, they refer to other authors who were interested in and registered normal subarachnoid pressure, including Axel Key (1832–1901) and Gustaf Retzius (1842–1919), and Heinrich Quincke (1842–1922; see Frederiks and Koehler, 199720). Falkenheim and Nau- nyn described the production and resorption of CSF, as well as the influence of blood pressure and venous pressure, measured in dogs. They emphasized the term “brain pressure,” defining it as the pathological pressure in the CNS by abnormally increased subarachnoid pressure.16 They distinguished direct signs (such as pulse decelera- tion, slow irregular breathing, headache, loss of consciousness, cramps, and pupillary anomalies) from indirect signs (such as papilledema, and general mental and physical weakness). They were able to list approximately the same symptoms and were mainly interested in consciousness, respiration, and vasomotor changes. They only casually mention “anomalies of the pupil movement.”16 FIG. 3. From von Bergmann’s book (von Bergmann E: Die Lehre von Early French Experiments den Kopfverletzungen. Stuttgart: F Enke, 1880): “Approximately at 1 the areas are situated from which the oculomotor will be affected (elevation Although some early trepanation experiments were con of the upper lids, movement of the ball, dilation of the pupils, turning of ducted early in the 19th century, more serious French ex- the head to the contralateral side).”

J Neurosurg Volume 122 • February 2015 457

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC P. J. Koehler and E. F. M. Wijdicks periments had to await the second half of the century. Hen ri Duret (1849–1921; Fig. 4) in the mid-1870s studied cerebral vasculature15 and then commenced his experiments with respect to cerebral trauma, culminating in his famous 1878 doctoral thesis13,17 that, with the aid of David Ferrier, also appeared in the first volume of Brain.14 Duret wished to explain what exactly happened in commotion, compression, and contusion, terms that had been used for some time. One of the most important concepts he introduced was that of “choc céphalo-rachidien” (cepha- lospinal shock).33 Therefore, he investigated the effects of blows on the head, of increased ICP, as well as those of damage of the dura mater. Following one of his early 1877 CSF shock experiments in animals (no. IV: blow on the forehead), he observed loss of consciousness, tetany, rigid- ity, stertorous breathing, slow and then increasingly faster breathing, middle-wide pupils, and loss of sensitivity. A few days later the pupils became small and the animal died. Next to hemispheric damage, he also observed congestion in the brainstem:13 “The existence of hemorrhagic lesions in the superior part of the bulbar base [most probably IV ventricular base], proves that the blows to the skull may have a considerable effect on the bulbus. The bulbar lesions are localized at one of the way-outs of the CSF.” (Fig. 5). Duret mentioned that these bulbar sites contain the motor nuclei of the eye and facial muscle nerves. He related these pathological findings to what had been observed in similar cases, numerous times, with respect to facial and eye phenomena, including “convulsive dilatation and constriction of the pupils.” Duret’s studies led Kocher to apply the eponym “Duret’s hemorrhages.” Duret named the pathophysiological theory that of the “choc du liquide céphalo-rachidien” (CSF shock) and distinguished two FIG. 4. Henri Duret (1849–1921). phases: 1) the period of the actual shock, including tetany and resolution, and 2) a period of congestive and inflammatory reaction. During this first phase, the pupils contract.13 This phase may last from seconds to 15 minutes serted, Duret distinguished between the effects of the CSF depending on the strength of the blow: “Thus, at the mo- shock that could be stopped by puncture of the occipi- ment of the shock, and during some instants after that, it is toatlantoid membrane (by which CSF may be removed) probable that not a drop of blood passes through the cere- leading to recurrence of respiration, and the effects of in- bral vessels.”13 It is followed by the resolution phase. The creased ICP that only disappear after trepanation and re- muscle contractures disappear gradually. The animal re- moval of the wax leading to disappearance of the coma and mains comatose for a while, without movement or sensitiv- the dilated pupils.13 With repeated blows, he demonstrated ity and with rapid respiration. In light “shock” it recovers. pupillary constriction followed by dilation and death. He In severe “shock” the reactive period starts, i.e., inflamma- explained the constriction by the CSF shock (bulbar le- tory reaction. The animal remains somnolent or comatose. sion) and the dilation by the accumulation of blood around Duret explained the first period by reflex contracture, be- the third cranial nerve.13 The resolution phase of the shock cause of the rapid occurrence. He believed that this reflex period was explained by vascular disorders, starting with a contracture is caused by a disorder in the brainstem, in general spasm of the vascular system followed by spasm of particular the restiform bodies (with a high density of sen- the cerebral vessels. The movements of the brain (the pul- sory fibers in his opinion) injured by the CSF shock. He sations) also stopped for minutes. For the latter he referred believed it had been proven that a blow to the skull may to observations by others, among them von Bergmann, be transmitted to the brainstem, which he considered evi- who noted paleness of the brain (from general spasm) and dent because of the lesions of that organ. The lesion of the barely visible retinal arteries (from spasm of the cerebral restiform body was believed to result in a reflex tetany. All vessels). muscles were put into motion by the reflexive discharge: Duret compared his “choc céphalo-rachidien” with the muscles of the limbs, trunk, eyes, and pupils. The respira- apoplectic shock in stroke and extensively referred to the tory arrest was also due to contracture of the diaphragm work of his teacher Jean-Martin Charcot (1825–1893):13 and respiratory muscles.13 The phenomena observed in hu- “We lend from the lessons of our savant master professor man commotion were explained by this CSF shock. Charcot, the theory on apoplectic shock as it has formu- In another experiment in which epidural wax was in- lated in 1869 in the lectures at the Salpêtrière that will

458 J Neurosurg Volume 122 • February 2015

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC History of the fixed and dilated pupil

Duret tried to explain the theory by the extraordinary vascular supply of the vertebrobasilar system by numerous collaterals (“coeur basilaire,” or basilar heart). British Experimental and Clinical Contributions The British contribution was more clinical than experimental, although similar experiments were reported.

Cooper’s Experiments Pagenstecher and Duret both refer to the English surgeon Sir Astley Cooper (1768–1841),10 who investigated the effect of solid materials on the brain. The reference is found on the indicated page of a chapter on “Fracturen des Schädels” (17th lecture). In the original English text, Coo- per described how he trephined a dog, “took out a portion FIG. 5. From plate XIII, Fig. 37 in Duret’s book (Duret H: Études Expéri- of the bone ... separated the dura mater from the bone” and mentales et Cliniques sur les Traumatismes Cérébraux. Paris: Delahaye, compressed the dura with his fingers. At first there was no 1878): “Tear of the fourth ventricle by gelatin injection in the cranial cav- reaction, but upon further compression the animal showed ity (exp. II, p.14).” Figure is available in color online only. signs of pain, became comatose, and fell:9 “I kept him in that state for five or six minutes when, upon removing my follow.” Although it was already known that hemorrhages finger, he got up, turned round two or three times from exceeding a volume of 40–50 cm3 would result in coma, giddiness, and walked away apparently little worse for the that did not explain (initial) coma in smaller hemorrhag- operation.” An accompanying person noticed slowing of es:13 “We believe to be able to respond: that in the hemor- the pulse during the experiment. Pupillary changes were rhagic ictus and the traumatic shock, the mechanism of the not mentioned in this experiment, but he did refer to di- observed phenomena is identical.” Smaller hemorrhages lated pupils in clinical cases in lecture XVI “On injuries near the ventricles cause a CSF shock that damages the of the head”:9 “The pulse, however, is not slow unless the brainstem in a similar way as described in traumatic inju- body be at rest: for upon the slightest exertion it becomes ries. In the intracranial hypertension studies, the pressure exceedingly quick: the pupils are dilated...” However, was increased gradually and therefore, Duret reasoned, he does not mention whether they were fixed, and from hardly any phenomena of CSF shock are observed,13 but the circumstances it is not clear whether he is referring sometimes some pupillary constriction is noted. In most to the topic of this paper. He was already distinguishing experiments attention is given mainly to the effects on the concussion and compression of the brain, the latter from arterial tension and pulse. Before death, wide and dilated bone compression, extravasation of blood, or “formation 9 pupils were observed in most cases. The dilation of the pu- of matter within the skull.” In another lecture (XVII) he 9 pils is attributed to paralysis of the third cranial nerves.13 explained the symptoms of compression: “The breathing Duret was well aware of what was done elsewhere. He being stertorous, the pulse slow, and the pupils dilated; reproduced some experiments from the work of Pagen- ...when you then find a patient with the apoplectic stertor, stecher (numbers 32 and 33),44 i.e., those with respect to slow pulse, dilated pupils, it will generally happen that the epidural wax insertion at the right parietal area;13 pupil- brain is compressed.” lary dilation was noted, and the iris was hardly visible any- In his Lectures, Cooper described the symptoms of 8 more (in a dog). In the second experiment, the left pupil concussion, including coma: “the pupils of the eyes are was enlarged and the right one constricted, with the head generally natural; but if changed, both are a little dilated; turned to the right.13 After some time, both pupils become or sometimes one only.” In another case, “a friend of Lord constricted (soporose). The following days he noted dete- Nelson’s ... [who] fell from his horse,” Cooper noticed that rioration, changing pupils, and finally wide dilated pupils he “was totally insensible; the pupils were dilated.... He bilaterally. In experiment 39, wax in combination with oil was bled from the arm to a considerable extent.” Follow- was injected into the subarachnoid space on the left side, ing a temporary improvement, he deteriorated, “his eyes resulting in a dilated left pupil.13 The animal survived a became nearly insensible to light, though one of his pupils was still contracted ... the other ... dilated and immov- few days and the pupils became constricted bilaterally. 8 Duret compared the slower effects in his subarachnoid ex- able.” Dilated pupils are mentioned among symptoms of “compression of the brain” in several other cases in this periments with the rapid effects in Pagenstecher’s experi- 8 ments. Of further note is that Duret proposed that the cor- book. He rarely noted whether the pupils, if dilated, react- ed to light. In a comatose boy, however, he noted “pupils neal reflex is an excellent device to measure the degree of 8 compression: 13 “An excellent way of measuring the degree dilated, but contracted on exposure to light.” of compression, applying a sensible method, is the touch of the cornea... Indeed, the brainstem resists the longest time: Bright’s and Hutchinson’s Observations it is the ultimum moriens of the nervous centers, following Richard Bright (1789–1858) mentioned “pupils un- the pittoresque word of our erudite master M. Charcot.” equally dilated and contracted” among symptoms of con-

J Neurosurg Volume 122 • February 2015 459

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC P. J. Koehler and E. F. M. Wijdicks cussion,4 paying attention to the effect of light. He observed vations—some more enlightening than others—how were a traumatic case between 1828 and 1831.4 A 38-year-old these observations described in neurological textbooks man working at “a large wharf below London bridge” fell and who could make sense of it all? Table 2 demonstrates from a height of 11 or 12 feet. The following day his “lan- that dilated pupils were observed early, but its significance guage was incoherent and speech scarcely articulate, and and pathophysiological basis was not always understood. he complained of pain in the head.” He was bled, and the In most neurological textbooks (as described above; earlier third day “he is in a state of stupor, but may be roused to in surgical texts) the sign is found in chapters on apoplexy answer question.” The “muscles of the left side of the face and later, approximately after 1900, also in chapters on ce- are paralyzed... right pupil dilated.” Because of “increas- rebral trauma. Dilated pupils were noted earlier than fixed ing coma,” blood is taken from the temporal artery. He pupils. Pupil dilation and cortical localization were pre- died the sixth day and an autopsy was performed. An epi- sented by several authors, including Mills.38 He referred dural hematoma was found. In the discussion of this and to Ferrier’s centers on the “lateral surface of the brain of other cases, Bright did not seem to note any particularity a monkey:” “center for lateral movements of the head and about the ipsilateral dilation of the pupil. In general “the eyes with elevation of the eyelids and dilation of the pu- pupils [are] sometimes contracted, at other times dilated, pil.” Mills pointed to an area that can now be considered and acting quite irregularly under the stimulus of light.” In the frontal eye field. Similar descriptions are found in the another case involving a 20-year-old man with apoplexy, writings of Ross.48 The phenomena and localization cor- Bright described “pupils dilated, and did not contract respond to what von Bergmann (Fig. 3) found,53 probably when a candle was brought near them ... I ordered the temporal artery to be opened ...”4 indicating sympathetic widening of the eyes and pupil di- The clinical observations reported by Jonathan Hut lation by local irritation (see above). chinson (1828–1913) in 1867–1868 resulted in the eponym Following the period of extensive experimental research “Hutchinson pupil,” attributed to him first by Jacobsen in ICP, the prognostic significance of the fixed and dilated in 1886,18 when he described several cases with dilated pupil was soon recognized by authors of neurological text- and unresponsive pupils.28 From his clinical experience, books and its pathophysiological mechanism was some- Hutchinson was aware that “the diagnosis of compression times mentioned. Around the turn of the century, many is full of difficulty. On the one hand, compression is fre- books do and some do not mention dilated pupils and its quently suspected when it is not present, and on the other, prognostic significance, such as in apoplexy and trauma. it is sometimes overlooked when really there.”27 He tried to Part of the reason for inclusion or exclusion of this topic reason in which cases trepanation would be advisable and may be explained by the type of practice they were writing mentioned 4 types of pathophysiological mechanisms, in- for (chiefly clinical or outpatient clinic practices). In many cluding epidural blood, arachnoid blood, epidural abscess, books, other signs of coma (such as blood pressure, heart and “inflammatory effusions within the arachnoid or into rate, and motor phenomena) were considered more impor- the brain substance.” In the first situation, “the patient ... tant. In fact, if sections in textbooks on pupils were pres- becomes insensible; but he is pale, with dilated pupils, a ent, pupillary changes in tabes dorsalis, later recognized to rapid, feeble pulse, and irregular respiration ... the patient result from neurosyphilis, took much more space. will probably be dead in an hour.” He was aware of the “interval of immunity between the accident and the oc- Discussion currence of symptoms [which] has been long recognized as the chief indication of a ruptured meningeal artery.” He In his historical review on the subject, Eugene Flamm also referred to the fact that “the hemiplegia will be on attributed the first observations to Gersdorff’s Feldbuch the opposite side [of the blood-clot]; a fixed dilated pupil der Wundarztney (1517 and many subsequent editions), be- will, I think, generally be present on the same side ...”27 cause woodcuts by Hans Wächtlin suggested a large pupil In the “arachnoid cases,” where the blood was found un- ipsilateral to the impression fracture, in some cases com- der the dura, unequal pupils “will rarely be present” and bined with an abducted eye.18 Although several other signs “the patient ... may live longer.” Compression in the third of severe head injury have been noticed before and after and fourth pathophysiological conditions, Hutchinson re- that period, the author stated that, “yet well into the nine- alized, is very hard to recognize. In 1896, Leonard Hill teenth century no writer commented on the occurrence of summarized the literature on experimental observations anisocoria in association with a mass lesion. Certainly no with respect to increasing cerebral pressure,24 noticing the one made the association with compression of the third effects on the pupils (“constriction of the pupils first on nerve.” One could argue, however, about Robert Whytt’s the compressed side, followed by dilation”24), but did not description in 1763 of a 5-year-old boy with fixed pupils, pay attention to the pupils in his own experiments. He also unresponsive to light, who at autopsy had a fluid collection referred to his compatriots Spencer and Horsley (1891),50 compressing the optic thalamus.41,54 Moreover, Whytt not- who performed experiments with increased ICP. Although ed “for, as in syncope, apoplexy, or at the moment of death, describing the effects on the heart, blood pressure, and res- when the eye is quite insensible to external objects, the piration, they did not mention the effect on the pupils. pupil is always greatly dilated.”54 One wonders whether he understood the prognostic significance of the sign during Appearance of the Fixed and Dilated Pupil in his life and it is doubtful whether he comprehended the pathophysiology. Cooper, in the 1830s, only mentioned di- Textbooks lated pupils, without referring to whether they remain fixed With this smattering of experimental and clinical obser- on light, which is of particular importance if dilation is no-

460 J Neurosurg Volume 122 • February 2015

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC History of the fixed and dilated pupil

TABLE 2. Mention of dilated and fixed pupils in early medical and ter is the work of von Bergmann: with respect to the local- later neurological textbooks ization of the lesion responsible for pupil dilation, he was Pupil confused by the effect of local (frontal) cortical irritation Authors & Year Dilation* Fixed Pupil resulting in epileptic phenomena and the effects of oculomotor nerve lesions. In most cases, however, “fixed” was 19th century either mentioned or it could be interpreted as such by the Cheyne, 1812 2† Yes combination of other signs, with the present knowledge. Rostan, 1823 1 ? (L’oeil fixe, p. 58) Naunyn and Schreiber already noticed the association Romberg, 1840–1846 — No between increased ICP, pupillary dilation, bradycardia, 40 Trousseau, 1882 — No and increased blood pressure (and the opposite in 1881). Table 2 reviews whether authors mentioned light-fixed pu- Ross, 1882 1‡ No pils and had insight into the pathophysiology of pupillary Hammond, 1872 2 Yes dilations. Our reading of the literature is that insight into Charcot, 1890 — No§ the mechanism of acute pupillary changes originated in Hughlings-Jackson, 1876 — No¶ the period in which animal experimentation with ICP be- Gowers, 1893 2 Yes gan. The beginning of the experiments on ICP coincides Osler, 1893 2 Yes with the increasing importance of the experimental method in medicine around the mid-19th century, such as the Dana (in Dercum), 1895 1 No work by Claude Bernard (1813–1878) and Rudolf Virchow Keen (in Dercum), 1895 1 No (1821–1902). Von Leyden’s 1866 paper appears to be the Mills, 1898 3** Yes first in which experimental studies prove the association Church & Peterson, 1899 — No between fixed dilated pupils and increased ICP. Various Oppenheim, 1900 2 Yes methods for increasing intracerebral pressure were used. 20th century We chose to discuss experiments and clinical material ac- Starr, 1907 2 Yes cording to country, although it became obvious that several investigators also referred to papers published in other Purves-Stewart, 1908 2 No countries. Remarkably, but not unexpectedly, experiments Marie, 191136,39 2 Yes were mainly conducted in Germany and France, although Dejerine, 1914 2 Yes Hill and Spencer/Horsley performed experiments in this Lewandowsky, 1910 2 Yes†† field in England in the last decade of the 19th century. Jelliffe & White, 1919 — No Duret went further than his German colleagues, wishing Bouman & Brouwer, 1930 2 Yes to investigate commotion as well as compression. He explained the pupillary phenomena by “choc céphalo-rachi- Jaensch-Essen (in Bumke & Foer- 2 Yes dien” leading to damage of the superior part of the bulbus ster), 1936 (base of the fourth ventricle). He distinguished between Wilson, 1940 2 Yes a shock phase, during which the pupils constrict, and a Biemond, 1961 2 Yes congestive/inflammatory phase causing pupillary dilation, Plum & Posner, 1966 3 Yes which he attributed to paralysis of the third cranial nerves. Zülch et al., 1974 3 Yes With respect to the significance of the fixed dilated pupil during the 19th century, a gradual increase from * Classification of understanding pupil dilation: 1 = casual mention, probably clinical observation and associations, to experimental ex without knowledge of prognostic significance; 2 = recognition of prognostic significance; 3 = 2 + understanding the pathophysiology (third nerve compres- planation and pathophysiological insight, can be demon- sion). strated. Cooper in the 1830s conducted some primitive † Cheyne mentions constriction and dilatation; on page 13:6 “Thus we do not experimental work, but without mentioning the pupils. despair until the pupil ceases to contract. With any return of sensibility our He did observe dilation in clinical cases. Bright, around hopes rise, and with the diminution of it they are destroyed.” 1830, was only partially aware of its significance and ob- ‡ Dilated and fixed pupil mentioned, e.g., in oculomotor nerve paralysis but viously before the period of knowledge of ICP, bled his not in hemorrhage or coma. patients. Hutchinson (1867–1868) was fully aware of the § We looked in this book on stroke, only brief clinical information, with an significance of the fixed and dilated pupil, but realized that emphasis on postmortem; other books are mainly outpatient/nontraumatic patients. this sign was not always reliable to lead the surgeon. After ¶ This is not an ordinary textbook; many chapters/papers on epilepsy. the mid-19th century, when the experimental method was ** Mentions “Hutchinson pupil” in “supradural hemorrhage.”37 fully accepted, von Leyden (1866) was the first to establish †† Refers to the work of von Leyden, Naunyn, Schreiber, and Falkenheim; experimentally a relation between fixed dilated pupils and only casual mention. increased ICP. If the pupils were asymmetrical, it could be attributed either to increased ICP or to an oculomotor nerve lesion. Pagenstecher (1871) extended the knowledge ticed bilaterally. In several publications, it was not always on this subject by painstakingly studying consecutive pu- clear whether investigators just found dilation, or dilation pil phenomena with increasing pressure. Duret (1878) was in combination with fixation to light. Pupil dilation could, important in the way that he distinguished between trau- in some cases, be attributed to sympathetic activation due matic injury and commotion with brainstem lesions from to pain, fear, or epileptic discharges. An example of the lat- lesions in which ICP was increased; this distinction had

J Neurosurg Volume 122 • February 2015 461

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC P. J. Koehler and E. F. M. Wijdicks differing effects on the pupils (constriction and dilation, 4. Bright R: Diseases of the Brain and Nervous System. Re- respectively). The first traumatic injury/commotion was ports of Medical Cases, Vol 2, Part 1. London: Longman, compared with reversible coma in (hemorrhagic) stroke Rees, Orme, Brown & Green, 1831 5. Charcot JM: Hémorrhagie et Ramollisement du Cerveau. and the latter to larger hemorrhages. The surgeon von Métallothérapie et Hypnotisme, Électrothérapie. Oeuvres Bergmann (1880), in experiments as well as clinical cases, Complètes, Vol 9. Paris: Bureaux du Progrès Médical, 1890 emphasized the significance of the ipsilateral dilation. He 6. Cheyne J: Cases of Apoplexy and Lethargy: With Obser- delineated the difference between the extent of the pres- vations Upon the Comatose Diseases. London: Underwood, sure increase and its duration. Most probably, he was con- 1812 fused between the general effects of epileptic phenomena 7. Church A, Peterson F: Nervous and Mental Diseases. Phila- (including sympathetic widening of eyes and pupil dila- delphia: Saunders, 1899 8. Cooper A: The Lectures of Sir Astley Cooper. On the tion) by local irritation and the effects of oculomotor nerve Principles and Practice of Surgery with Additional Notes lesions. Naunyn and Schreiber (1881) emphasized and un- and Cases, ed 3. Tyrell F, ed. Boston: Lilly & Wait, 1831, derstood the relationship between increased ICP, noted by Vol 1 pupil dilation and decreased pulse frequency, and blood 9. Cooper A: The Principles and Practice of Surgery. Lee A, pressure. They wrongly explained the relation by localiza- ed. London: E Cox, 1836, Vol 1 tion in the medulla oblongata, but were well aware that 10. Cooper A: Theoretisch-Praktische Vorlesungen über blood pressure should not be decreased but increased. The Chirurgie. Lee A, von Schütte J, eds. Leipzig: T Fischer, 1837 textbooks we studied confirm that, although the authors 11. Dana CL: Focal diseases of the brain, in Dercum FX (ed): of textbooks were aware of the prognostic sign, dilation Textbook on Nervous Diseases. Philadelphia: Lea Brothers was not always related to fixed dilated pupils and that the and Co, 1895, p 451 pathophysiological basis of the fixed dilated pupil was not 12. Dejerine J: Sémiologie des Affections du Système Nerveux, understood for a long time. ed 2. Paris: Masson, 1914, p 9 When studies on increased ICP are described, papers 13. Duret H: Études Expérimentales et Cliniques sur les often start with Cushing’s 1900–1901 experiments in Traumatismes Cérébraux. Paris: Delahaye, 1878 Berne, and with a few exceptions19 do not discuss the ex- 14. Duret H: On the role of the dura mater in cerebral trauma- tism. Brain 1:29– 47, 1878 perimenters described above. In his correspondence to his 15. Duret H: Recherches anatomiques sur la circulation de friend, the Swiss physician Arnold Klebs, Cushing later l’encéphale. Arch Phys Norm Pathol 1:664–693, 919–957, 19,21 admitted: “As a matter of fact, when I wrote that paper 1874 in Kronecker’s laboratory I had very little chance to study 16. Falkenheim H, Naunyn B: Uber Hirndruck. Leipzig: the literature; if I had, I’d probably never have done the Hirschfeld, 1887 work.” 17. Feinsod M: Neurognostics question: a life in neuroscience, The 20th century would bring more insight into the pu- surgery, and faith. J Hist Neurosci 19:365–366, 415–418, 2010 pillary mechanisms. An important advance came in 1939, 18. Flamm ES: The dilated pupil and head trauma 1517-1867. when Reid and Cone published their experimental study Med Hist 16:194–199, 1972 in anesthetized monkeys after infusing Ringer’s solution 19. Fodstad H, Kelly PJ, Buchfelder M: History of the Cushing through trephine holes. In their experiment they could reflex. Neurosurgery 59:1132–1137, 2006 induce and reverse pupillary dilation through manipula- 20. Frederiks JAM, Koehler PJ: The first lumbar puncture. J Hist tion of the ICP. The oculomotor nerves were found to be Neurosci 6:147–153, 1997 compressed by the extruded hippocampal gyrus in most 21. Fulton JF: Harvey Cushing. A Biography. Springfield: Charles C Thomas, 1946, pp 176–193 cases. Jennett and Stern replicated the experiment in cats. 22. Gowers WR: A Manual of Diseases of the Nervous System, Ropper suggested acute angulation of the third cranial ed 2. London: Churchill, 1893, Vol 2, p 99 nerve over the clivus due to displacement of the brainstem 23. Hammond WA: Treatise on Diseases of the Nervous Sys- in an autopsy study, which confirmed an earlier study by tem, ed 2. New York: Appleton, 1872 Fisher-Brügge, who coined the term “Das KlivusKanten 24. Hill L: The Physiology and Pathology of the Cerebral Cir- Syndrome,” (the edge of the clivus syndrome). How the culation: An Experimental Research. London: Churchill, opposite pupil enlarges with mass effect has also not been 1896 resolved and Ropper suggested a bilateral central (at the 25. Holman E, Scott WMJ: Significance of unilateral dilatation and fixation of pupil in severe skull injuries. JAMA nucleus level) third cranial nerve damage. Clinicians have 84:1329–1332, 1925 accepted fixed and dilated pupils as part of “herniation” 26. Hughlings-Jackson J: On epilepsies and on the after-effects and simply a consequence of increased ICP. Despite the of epileptic discharges (Todd and Robertson’s hypothesis) first experimentations in the 1800s and more work in the (1876), in Taylor J (ed): Selected Writings of John Hugh- 1900s, no definitive answer as to its true mechanism is lings Jackson. London: Hodder & Stoughton, 1931, Vol 1, pp known. 135–161 27. Hutchinson J: Three lectures on compression of the brain, in Clark A, Down, Hutchinson, et al (eds): Clinical Lectures and Reports by the Medical and Surgical Staff of the References London Hospital. London: Churchill & Sons, 1867, Vol 4, 1. Biemond A: Hersenziekten; Diagnostiek en Therapie, ed pp 10–55 3. Haarlem: Bohn, 1961, pp 443–451, 638–670 28. Jacobson WHA: On middle meningeal haemorrhage. Guys 2. Bliss M: Harvey Cushing. A Life in Surgery. New York: Hosp Rep 43:147–308, 1886 Oxford University Press, 2005 29. Jaensch-Essen PA: Pupille, in Bumke O, Foerster O (eds): 3. Bouman L, Brouwer B (eds): Leerboek der Zenuwziekten. Handbuch der Neurologie. Berlin: Springer, 1936, Vol 4, pp Deel II, 2E Gedeelte. Haarlem: EF Bohn, 1922–1930, p 15 267–339

462 J Neurosurg Volume 122 • February 2015

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC History of the fixed and dilated pupil

30. Jelliffe SE, White WA: Diseases of the Nervous System. A 47. Romberg MH: Lehrbuch der Nervenkrankheiten des Textbook of Neurology and Psychiatry, ed 3. New York: Menschen. Berlin: Duncker, 1840–1846 Lea & Febiger, 1919 48. Ross J: A Treatise on the Diseases of the Nervous System. 31. Keen WW: Surgery of the brain, spinal cord, and nerves, in New York: William Wood, 1882, Vol 2 Dercum FX (ed): Textbook on Nervous Diseases. Philadel- 49. Rostan L: Recherches sur le Ramollisement du Cerveau, phia: Lea Brothers and Co, 1895, p 981 ed 2. Paris: Béchet, 1823 32. Kocher T: Hirnerschütterung, Hirndruck und chirur- 50. Spencer W, Horsley V: On the changes produced in the circu- gische Eingriffe bei Hirnkrankheiten. Specielle Patholo- lation and respiration by increase of the intra-cranial pressure gie und Therapie, Vol 9. Nothnagel H, ed. Vienna: Hölder, or tension. Phil Trans R Soc Lon B 182:201–254, 1891 1901 51. Starr MA: Organic and Functional Nervous Diseases, ed 33. Koehler PJ, Wijdicks EF: Historical study of coma: looking 2. New York: Lea Brothers and Co, 1907, p 492 back through medical and neurological texts. Brain 131:877– 52. Trousseau A: Clinique Médicale de l’Hôtel-Dieu de Paris, 889, 2008 ed 6. Paris: Baillière, 1882, Vol 2, p 80 34. Lewandowsky M: Die Verletzungen des Gehirns und des 53. von Bergmann E: Die Lehre von den Kopfverletzungen. Schädels, in Lewandowsky M (ed): Handbuch der Neurolo- Stuttgart: F Enke, 1880 gie. Berlin: Springer, 1910, pp 48–50 54. Whytt R: An Essay on the Vital and Other Involuntary 35. Leyden E: Beiträge und Untersuchungen zur Physiologie und Motions in Animals, ed 2. Edinburgh: Balfour, 1763 Pathologie des Gehirns. Virchows Arch 37:519–559, 1866 55. Wilson SAK: Neurology. Bruce AN, ed. London: Arnold, 36. Marie P: La Pratique Neurologique. Paris: Masson, 1911 1940, p 1070 37. McHenry LC: Garrison’s History of Neurology. Spring- 56. Zülch KJ, Mennel HD, Zimmermann V: Intracranial hyper- field, IL: Thomas, 1969 tension. Handb Clin Neurol 6:89–149, 1974 38. Mills CK: The Nervous System and Its Diseases. Philadel- phia: Lippincott, 1898 39. Moutier F: Apoplexie et coma, in Marie P (ed): La Pratique Neurologique. Paris: Masson, 1911, p 179 40. Naunyn B, Schreiber J: Über Gehirndruck. Leipzig: Vogel, 1881 Author Contributions 41. Norman JM: Morton’s Medical Bibliography, ed 5. Alder- shot, UK: Scolar Press, 1991 Conception and design: both authors. Acquisition of data: 42. Oppenheim H: Diseases of the Nervous System. Mayer EE, Koehler. Analysis and interpretation of data: Koehler. Drafting trans. Philadelphia: Lippincott, 1900, p 504 the article: Koehler. Critically revising the article: both authors. 43. Osler W: The Principles and Practice of Medicine. New Reviewed submitted version of manuscript: both authors. York: Appleton, 1893, p. 873 Approved the final version of the manuscript on behalf of both 44. Pagenstecher F: Experimente und Studien über Gehirn- authors: Koehler. Study supervision: Wijdicks. druck. Heidelberg: Winter, 1871 45. Plum F, Posner J: The Diagnosis of Stupor and Coma. Correspondence Philadelphia: Davis, 1966 Peter J. Koehler, Department of Neurology, Atrium Medical 46. Purves-Stewart J: The Diagnosis of Nervous Diseases, ed 2. Centre, P.O. Box 4446, 6401 CX Heerlen, The Netherlands. London: Arnold, 1908 email: [email protected].

J Neurosurg Volume 122 • February 2015 463

Unauthenticated | Downloaded 09/26/21 12:22 AM UTC