Chapter 19: Argyll Robertson Pupils

CHAPTER 19 Midbrain Syndromes: Argyll Robertson Pupils CONTENTS A. Summary . . . . . . . . . . . . . ............. 1. Appearance . . . . . . . . . ............. 2. Etiology and Clinical Significance ....... 3. Mechanism ...................... B. Historical Background ................. 1. The State of Knowledge in Argyll Robertson's Time .................. 2. The Question of Syphilis ............. C. Appearance ........................ 1. Pupil Size ....................... 2. Completeness of Light Rigidity ........ 3. Extent of Near-Vision Contraction ...... 4. Integrity of Vision ................. 5. Papillary Reflex Dilation ............ 6. Bilateral, Unilateral, and Asymmetric Syndromes ...................... 7. Iris Changes ..................... 8. Phenomena Discussed in Connection with the Argyll Robertson Syndrome ........ 9. Reactions to Drugs ................ 10. Accommodation ................... 11. Clinical Course ................... D. Etiology ........................... 1. Syphilis ........................ 2. Nonspecific Infections of the Nervous System ......................... 3. Diabetes Mellitus ................. 4. Multiple Sclerosis ................. 5. Dejerine-Sottas's Hypertrophic Neuritis, Charcot-Marie-Tooth's Disease, and Similar Conditions ................ 6. Alcoholism ...................... 7. Syringomyelia .................... 8. Tumors and Cerebrovascular Disease ... 9. Trauma to the Eye or Orbit and Apparently Spontaneous Occurrence of 956 956 957 957 958 958 958 959 959 961 966 966 967 968 969 971 971 975 975 975 975 975 976 980 980 980 980 980 Dissociated Pupils ................. 10. Herpes Zoster .................... 11. Head Trauma and Other Impairment of the Third Nerve .................. 12. Other Causes . . . . . . . . . . . . . . . . . . . 13. Incidence and Characteristics of Argyll Robertson Pupils in Our Unselected Patient Group .................... E. Site of the Lesion and Mechanism of the Syndrome .......................... 1. Damage in the Cervical Cord .......... 2. Damage in the Afferent Path of the Light Reflex .......................... 3. Damage in the Efferent Path of the Light Reflex .......................... (a) The Oculomotor Nucleus .......... (b) The Efferent Third Nerve .......... (c) The Ciliary Ganglion or Ciliary Nerves ....................... (d) Damage in the Eye .............. (1) Iris Damage ................ (2) Assumption of Intraocular Ganglion Cells .............. (3) Vascular and Mechanical Theories ................... 4. Damage in the Intercalated Midbrain Neuron ......................... (a) Experimental Evidence ............ (b) Pathologic Evidence .............. (c) Clinical Evidence ............... 5. Mechanism of the Miosis ............. (a) Sympathetic Paralysis ............ {b) Sphincter Contraction ........... F. Conclusions on Probable Site and Mechanism ....................... 982 983 983 . 983 983 988 988 989 989 989 991 991 992 992 992 994 995 996 996 998 998 998 1000 .1001 A. Summary 1. Appearance Patients with the Argyll Robertson syndrome typically have small pupils that are often distorted. In darkness they are always smaller than normal, while in bright light the miosis is not always striking because these pupils react poorly (if at all) to light. In contrast, they do contract to near-vision efforts: within the mechanical limitations imposed by the miosis, the near-vision reactions are often brisk and extensive. However, it is not true that they are always "normal or better than 956 normal," as has been said in the literature. It is perfectly proper to call a case "Argyll Robertson" even when the near-vision reactions are impaired, as long as they are more ample than the patient's best light reflex. The deciding feature is the dissociation between the lightand near-vision contractions. Some authors have tried to limit the meaning of the eponym by excluding all cases without tight miosis, all those with imperfect near reactions, and those with traces of light reflexes still present. But these distinc- 19. Midbrain Syndromes: Argyll Robertson Pupils I 957 tions are meaningless: the anatomic area involved is small, and there are many gradations of the deficit. Even the reactions in the patient's right and left eye may differ in the degree of impairment of the light reflex or of the contraction to near vision. When a patient with Argyll Robertson syndrome stops looking near, the pupils redilate briskly. Watch for this movement: it distinguishes an Argyll Robertson pupil from a tonic pupil, which will remain stuck in miosis for some time after the near-vision effort is discontinued. Contrary to many statements in the literature, Argyll Robertson pupils react well to mydriatic eyedrops unless the iris has been damaged by the disease process. Reflex dilation to sensory stimuli also is often extensive and brisk. The Argyll Robertson syndrome is bilateral in about 80 to 90% of patients, but strictly unilateral cases do occur; and many times the pupils are unequal in size or in reactions because the right and the left side are affected in different degrees. Argyll Robertson in his original publications had said that the retina of his patients was "quite sensitive to light," and therefore it was argued that the eponym should not be used for patients with any visual defect whatever. But this goes too far. The important point is that retinal function should not be damaged sufficiently to explain the poor light reflexes. Accommodation typically is normal in patients with Argyll Robertson pupils. These pupils are closely related to fixed, miotic pupils, both symptomatologically and clinically, and Argyll Robertson pupils many times have been observed to develop into spastic miotic pupils by losing their remaining near-vision reactions. 2. Etiology and Clinical Significance Before the development of modern methods of antiluetic treatment, most patients with Argyll Robertson pupils had syphilis of the central nervous system, especially tabes dorsalis and general paresis. The pupillary syndrome was therefore often said to be an unfailing sign of neurosyphilis. This was, however, never true and has become even less so since antibiotic therapy for syphilis became available. Like all other pupillary signs, the Argyll Robertson syndrome indicates the location of a lesion and not the etiology of the damage, although, of course, certain disease processes have affinities for certain locations. Argyll Robertson pupils have been described in various kinds of encephalitis (especially von Economo's disease); in diabetes mellitus; in Dejerine-Sottas's hypertrophic neuritis; in Charcot-Marie-Tooth's disease, and similar conditions; in tumors, cerebral hemorrhages, or sclerotic plaques affecting the rostral midbrain; rarely after trauma involvingthe rostal brainstem; and (somewhat questionably) in chronic alcoholism. Argyll Robertson pupils also have been reported as associated with herpes zoster, trauma of the eye and orbit, and trau- matic or other involvement of the third nerve. But in the first two of these patient groups the Argyll Robertson syndrome was confused with the tonic pupil syndrome, and in the third, oculomotor "misdirection dyskinesia" was mistaken for the Argyll Robertson pupil. The Argyll Robertson syndrome does not prove that an active disease process exists at the time it is found: it may be merely a residual sign of a previously arr~sted disease, and quite frequently the cause of the pupillary defect cannot be determined. In such cases it is tempting to ascribe it to any disease the patient may have had. Because of the increasing incidence of nonsyphilitic Argyll Robertson pupils in recent years, a tendency has developed to discount the possibility of syphilis when the pupil syndrome is found. But in view of the overwhelming prevalence of syphilis in patients with Argyll Robertson pupils throughout the century since the syndrome was discovered, it appears a more conscientious course to go to great lengths in trying to detect or to disprove neurosyphilis in these cases (see Chapter 31). 3. Mechanism A number of opposing theories have been proposed over the past century about the mechanism of the syndrome and about the seat of the responsible lesion. Each of these was held with firm conviction by many authors. These discussions were long-winded, acrimonious, and exceedingly complex. But many of the supporting arguments were based on incomplete anatomic or physiologic concepts current at the time they were brought forth; or they perpetuated assumptions that had been reasonable at an earlier time but had since been disproven. Thus the Argyll Robertson syndrome has been said to be due to a defect in the cervical spinal cord; the afferent path of the light reflex; the intercalated neuron in the rostro-dorsal midbrain; the oculomotor nucleus; the efferent path in the third nerve; the ciliary ganglion, or the ciliary nerves in the iris. And the miosis which usually accompanies the Argyll Robertson light-near dissociation 1 was said to be caused by impairment of the sympathetic innervation of the pupillary dilator, or by cholinergic impulses to the sphincter muscle. We have surveyed the profusion of existing reports and opinions on this subject and, by a process of elimination, have confirmed our previous conviction (and that of many others) that the lesion responsible for the light-near dissociation is located in the rostral midbrain, while the miosis is caused by an abnormally increased sphincter tone, secondary to disinhibition of the Edinger-Westphal nucleus. In the pure Argyll Robertson syndrome, that is, without damage to the iris or other parts of the pupillary pathways or centers, the sympathetic innervation of the eye remains intact. 1. The term light-near dissociation is used throughout this book to mean the combination of poor or absent light reflexes with more extensive pupillary contractions to near vision. 958 I IV. Pupillary Pathology: Symptomatology B. Historical Background In 1869, D. Argyll Robertson published two famous papers in which five patients were described. AJI of them suffered from " pinal disease" (tabes dorsalis) and they howed a curiou phenomenon: "In all of them there wa marked contraction of the pupil, which differed ~rom ~~o i d_ue to other cau es, in that the pupil was m en 1t1veto light, ?ut contracted still further during the act of accommodation to near objects." While mall, fixed ~upils, often distorted or unequal, were known to occur m patients with tabes dorsafis and general paresi (see Table 31-2), the unusual dissociation ?ffunction:-:-that is, pupils that were fixed to light de p1te good v1 10n and yet contracted readily upon accommodation-had not been seen before. 2 But now it appeared that this wa quite common in the dreaded " pinal di ease." Argyll Robert on's reports drew immediate attention and were soon confirmed by others (Knapp, 1872; Leber, 1 72; and later authors). Thus was born the "Argyll Robert on syndrome" that was to become "the mo t famou , the mo t di cussed and the least understood of all pupillary phenomena' (Walsh and Hoyt 1969). ' Ever since the di covery of the syndrome, its cause, its mechani m, the location of the responsible lesion, and e~en the definition of the term have been subjects of disagreement. A time progressed the maze of conflicting report and hypotheses grew in volume. Many thousand of cases were described in more than twentyfive hundred publications. Adherents of conflicting schools of thought heaped up arguments in support of their opinions. These were challenged and defended in heated and repetitive debates which often failed to shed much light upon the questions at hand but, to the contrary, confused them more. Finally, the sprawling thicket of interwoven discussions had become so complex as to render clear thought impossible. In 1969 I reviewed this literature, sifting and sorting previous statements and tracking the various theories to their sources in order to find out which of them were based on fact and which on assumption; how they were related to the basic concepts current at the time they were proposed; and, finally, how they were able to stand up in the light of the anatomic, physiologic, and clinical discoveries made since Argyll Robertson's time. Thus brought into focus, the problem became less difficult than it had at first appeared. 3 2. An earlier report by von Graefe ( 1856) on a patient with disso~ia~ed light and near-vision reactions and Chiarugi's descnpt1on ( 1793) apparently had gone unnoticed. 3. The tables included in this chapter were taken from the 1969 review. r have not brought these tables up to date because first, the flood of perennial publications about the syndrome has begun to recede (fortunately), and second, more recent publications on one or the other aspect of the condition did not add materially to what has been said many times before. Some new papers are included in the Bibliography. 1. The State of Knowledge in Argyll Robertson's Time The discussions grew out of hand for the following reasons. In 1869, only a few of the facts needed for an understanding of the Argyll Robertson syndrome were known (Table 19-1). Early attempts at explaining its nature and speculations about the probable site of the lesion were thus based upon still limited (and partly faulty) anatomic and physiologic concepts. Later findi?gs did not fit these concepts, and secondary assumptions, offered to explain the discrepancies, compounded the difficulty. Two chief obstacles lay in the path to a solution of the problem: first, the complete Argyll Robertson syndrome had never been produced experimentally in animals, and second, numerous pathoanatomic studies did not reveal a consistent, discrete defect responsible for it. Patients who die from central nervous system syphilis usually have a great deal of diffuse brain damage, and since the pupillary fibers are relatively few, the proverbial search for the needle in the haystack remained unsuccessful. This lack of positive proof left open only the road of speculation, which was doubly tortuous due to the many unploughed fields through which it ran: naturally each generation's view was limited by the horizon of its time. 2. The Question of Syphilis The Argyll Robertson syndrome was an outstandingly frequent objective sign in tabes dorsafis,general paresis, and syphilis of the central nervous system. This became plain soon after its discovery, and thus the pupillary syndrome became involved in a long and bitter quarrel about the cause of tabes and of general paresis. Were these two deadly conditions separate diseases, or were they merely different aspects of neurosyphilis? This sad chapter will be dealt with later (see Chapter 31). As to the Argyll Robertson syndrome, its appearance and its course were the same in general paresis, in tabesdorsafis, and in lues cerebri,in children as well as in adults. What is more, it was virtually limited to these three diseases. It was thus both a connecting link between them and a mark that set them apart from other neurologic and psychiatric disorders. Argyll Robertson pupils often appeared years or even decades before the outbreak of the full-blown disease (Table 19-2); and, unlike the early, fleeting external ophthalmoplegias, the pupillary syndrome, once established, tended to persist. It therefore could alert the physician to the danger brewing; it could clarify cases with otherwise vague and erratic complaints; and sometimes it indicated previously unsuspected syphilitic involvement in certain diseases (for example, syphilitic aortitis). No wonder that the interest in this syndrome grew by leaps and bounds, and that the discussions about it were conducted with unusual heat and tenacity. 19. Midbrain Syndromes: Argyll Robertson Pupils Table 19-1. s / 959 The state of knowledge in Argyll Robertson's time BJECT A. PARASYJ\lPA TllETIC established (about) 1 G9 19G9 - - - + + + + + 1180-1960 1 701 70-1900 1 80-1913 1 70-1900 - + 1 7n .1 n••n 1 :80-1912 1 :89-1933 1 70-193-1 b85-1890 I:\"NERVATION 1. Afferent 2ath of light reflex identity of retinal reccotors identity of rrnne:l ion cells and fibers in on tic nerve hem idecussation of fibers in optic chiasm course in optic tract, and from there to midbrain role of hemispheres, especially for vision 2. :\lidbrain neurones existence of intercalated neurone central hemidecussation of punillarv path location of svnaose for intercalated neurone identitv of sphincter nucleus mechanism of inhibition of sphincter nucleus :3. Efferent path location of ouu il fibers within third nen·e existence of cell station in ciliarv ,rnnrdion details of anatomy of ciliary gane:lion existence of sphincter muscle short ciliary nerves to sphincter muscle B. SY:\IPATIIETIC + /+) - + + - + + + + + + + + 19-18-196 l 1 oo-vqo 1 80-1900 1 00-18--10 1 00-18-10 I:s;:'\ERVATIO:'\ origin of sympathetic nerves from spinal cord syml)athetic innervation of blood vessels svmuathetic l)ath via cervical chain identity of l)upil dilator muscle sympathetic representation in medulla syml)athctic representation above medulla eclation of dicncel)halic centers to cortex descending path via midbrain, medulla and cord existence and location of hcmidccussation in this path C. GE:'\ERAL - PERTINEl\T + + + - + + + + + + - + ++- + 1851-lb53 1800-1855 1727 1890-1910 lb55-1860 1909 1909-1920 1912-196-1 1912-1963 SUBJECTS relation between tabcs, general paresis and syphilis control of motor functions bv cerebral hcmisnhercs natu L"C of rec iProcal inhibition t,1·0-neu1·onc oni:ani;:ation of autonomic nervous system existence of cholinergic and adrenere:ic nerves mechanism of humoral transmission of nerve impulses phenomena of denervation hyperscnsitiv ity phenomena of regeneration of injured nerves innervation ol adrenal gland release of hormones from adrenal e:land existence of non-adrenal adrenergic substances mechanism of action ol eserine, atropine, cocaine, etc. From Loewenfeld, Survey Ophthal. 14(1969):199-299 +=essentially known; - = essentially unknown; (+) some details - - - + + + + + + + + + + + + 1853-1901:s 1873-1930 1895-1905 1880-1900 1902-1!.)23 1900 1921 1900-19-1., 1900-19-17 1900-192.3 lb9'l 1925 1930-1960 ? 1960 unclear. C. Appearance 1. Pupil Size All five of Argyll Robertson's original cases had "spinal miosis." But soon many authors encountered patients with light-near dissociation but with larger pupils (Table 19-3). In fact, the cases without marked miosis outnumbered the ones with it (Table 19-4). And both small and large dissociated pupils seemed to have the same pathologic significance: they went with tabes, general paresis, or lues cerebri in the vast majority of cases. The definition of "Argyll Robertson" was therefore broadened to include the dissociation alone without the miosis ("reflex rigidity"). As time went on, however, it was found that some patients with large, dissociated pupils did not fit the Argyll Robertson pattern at all: their pupil movements were quite different, and the clinical history and course of their disease were not the same. These patients did not have syphilis. Some of them had midbrain tumors; in others the pupil syndrome developed after trauma to the head, the eye, or the orbit, or apparently spontaneously, without known cause. Many authors therefore insisted that "true" Argyll Robertson pupils had to be miotic, and they were pathognomonic of neurosyphilis, while "false" or "pseudo" Argyll Robertson pupils could be 960 I IV. Pupillary Pathology: Symptomatology Table 19-2. YEAR The Argyll Robertson pupil as the earliest physical sign of tabes (T) or general paresis (GP) A THOR DISEASE YEAR T 1876 1 76 1 76 1 79 1 83 1 K5 1 5 1 6 1 6 1 6 1 7 1 ~7 lb37 1 o lb lb .,9 1'91 1 92 Hs93 1 93 1 93 1 95 1 95 1 93 1 96 1 96 1 96 1 97 lb97 lb97 lb9b lb99 1900 1900 1900 Crichton-Browne Hempel Erb de Wecker v. Leyden Mendel l\Ioeli Frost Salim Thomsen Borel .i\'loeli Rumpf Forster Dillmann Schlitz Boedecker Grosz Knies Renaud Leimbach llirschl Boche Koeni!r Sieme rl inrr Thomsen \". Leyden & Goldsche ider :\Iobius Thomsen Schmidt- Rimoler Alexander D,,.i,-,dne Erb Hinschelwoocl From Loewenfeld, Survey Ophthal, DISEASE AUTHOR GP + + + + + + "T' 1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Donath Sulzer Mann Maradon 1901 1901 1902 1902 + + + + u,,., 1903 1906 1906 1907 1907 1910 Hll(I 1912 19H 1918 1919 1919 1921 1921 1923 192--i 1929 1929 1930 1931 1931 1931 1935 1935 1936 1936 194•1 19H 19--lcG 19·l9 + + LC + + + + + de Montyel Schwanecke Buttino Posev & Soiller Bumke Pilcz i\1ar!!.Ulies \VPilf"r Goldflam Behr Lutz Jelliffe & White Nieden Aboab Stalber!r l\Iemmersheimer Thavsen Last Luria Caso Kvrieleis Gifford & l\laver Maver Lae:rano·e & Larrranrre Lowenstein Jaensch Schaeffer & Leger Moore Stern l\Ierritt & a1. Jaffe np + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 14(1969):199-299 LC • 1ues cerebri. found in other diseases, and they were usually large (Table 19-5). The question of whether miosis was an essential part of the Argyll Robertson syndrome was debated exhaustively throughout the following decades. These controversies were caused partly by the attempt of many authors to make the syndrome an unfailing sign of neurosyphilis, and partly by confusion of the Argyll Robertson phenomenon with other pupil syndromes (see below). But mostly the conflict arose because the term "miosis" was used without regard to the conditions of observation. Clinical pupil examinations usually are done in room light which is at least bright enough to allow the observer to see the patient's iris clearly. This light stimulates the patient's retina, and if the pupils are normal, they become fairly small. Pupil diameters down to 2 or 3 millimeters therefore have been accepted as "physiologic" by many clinicians. In darkness, however, these same normal pupils become much larger. The Argyll Robertson pupil, on the other hand, does not contract to light and may look fairly large on clinical examination in room light. And since few clinicians use the instruments needed to observe the pupils in the dark, it is not generally appreciated that the Argyll Robertson pupil not only fails to contract to light but also fails to dilate in darkness, and in the dark reveals itself as indeed smaller than the normal pupil (Figure 19-1). The disagreements about inclusion or exclusion of the miosis in the definition of the Argyll Robertson syndrome could therefore be laid to rest if the statement were simply qualified: in darkness Argyll Robertson pupils are smaller than those of normal persons in the same age group. Most of the "medium" and "large" syphilitic dissociated pupils described in the literature would be included in this definition (for example, Table 19-6). And at the same time two facts would not be obscured. (1) In the Argyll Robertson syndrome there is a mechanism that keeps the pupils permanently smaller than they should be, considering their failure to respond to light. 19. Midbrain Syndromes: Argyll Robertson Pupils / Table 19-3. YEAR 1872 1873 1876 1877 1878 1878 1879 1879 1880 1881 1881 1881 1882 1883 1883 1885 1887 1889 1890 1890 1892 1892 1893 1894 1895 1895 1896 1896 1897 1898 1898 1899 1899 1900 961 Dissociated pupils with or without miosis AUTHOR YEAR Aldride:e Mobeche Hempel Vincent Coint Boy Erb Stewart Erb Bernhardt Remak Voigt Rehlen Gowers Mooius Moeli Moeli Berger Marie Marina Guillery Kornfeld & Bikeles Knies Briand Hillenberg Leimbach Simerka Thomsen v. Leyden Ingelrans Leszinsh de Schweinitz Thomas Dejerine From Loewenfeld, Survey Ophthdl. 1900 1900 1900 1900 1903 1903 1903 1904 1906 1906 1906 1906 1906 1908 1910 1911 1912 1912 1912 1914 1918 1921 1921 1921 1922 1923 1923 192-± 192-± 1924 1924 1924 1925 1926 AUTHOR YEAR Levinsohn Frenkel & Foerster Harris v. Leyden Collins Mott Sarb6 Bach Ferrier v. Ilinnel MUllerleile Nadal Posey & Sniller Stumm Weiler Bumke Rose Thomas Winaver Dejerine Wilson Foster Krambach Wilson Wilbrand & Saenger Holmes Li::ihlein Bramwell Fuchs l\1arnuez Paton Vuillaume Marauez Triossi 1927 1927 1927 1928 1928 1929 1929 1934 1934 1934 1935 1935 1935 1935 1935 1936 1936 1938 1938 1938 1939 1942 1946 1948 1949 1949 1956 1958 1959 1961 AUTHOR Barre Santonostaso Velter & Tournay Marquez Wilson Pires & Canha Rabinovitch Aliauo-Mazzei Editorial, J. A.M.A. Schaeffer Harris Lae:rane:e Lagrange & Lagrane:e Le Fever Tournay Orlando & Chile hilnitskv Schaeffer & Merigot de Treio-m, Rea Schaeffer & Merigot de Trei=v Velter Rocha Velter Mae:itot Parsons & DukeElder Duke-Elder Jelliffe & White Coe:a.n Sorsby Guillaumat & al. Huber 14(1969):199-299 (2) Other dissociated pupil syndromes do not, as a rule, show the same kind of spontaneous constriction. As will be seen later, these points are important for the consideration of the mechanism and site of the condition. 2. Completeness of Light Rigidity The "classic" Argyll Robertson pupil fails to react to light, both directly and consensually, as in the cases shown in Figure 19-2, 19-3, and 19-4. More commonly, residual light reflexes are found in pupillographic records (see Figure 19-5). Chiefly in an effort to restrict the definition of the syndrome and thus to bolster its "pathognomonic" nature for neurosyphilis, Behr and a number of later authors insisted that the light reflex had to be lost completely before the diagnosis could be made. But such a rigid definition would, in our experience, eliminate most of the cases; and it was based on clinical examinations with weak light sources. In the old examinations, candles, gas flames, and other weak light stimulators were used to test the pupils; and the remarkably high incidence of impaired light reflexes in some clinical statistics before 1900 may have been influenced by this practice. When modern flashlights are used to stimulate the patient's eyes, many Argyll Robertson pupils that might have been judged fixed to light in Behr's time do show residual light reflexes. Further, examination in darkness will bring out small light reflexes that cannot be elicited in ordinary room illumination. The narrow definition advocated by Behr and his school therefore cannot be maintained. In the first place, it fits only a few cases, and second, there are many patients with one pupil fixed to light and the other still reactive (Figure 19-6). Obviously the same disease process, affecting the same general area of the brain, causes the two closely related variations in response pattern, and it would hardly be sensible to call the one "Argyll Robertson" and the other not. The term partial Table 19-4. Relative frequency of miosis YEAR AUTHOR 1877 1879 1880 1881 1 2 1 3 1 5 1 7 1 9 1 90 1894 1 95 1 95 1 96 1 99 1900 1903 1903 1903 1927 1929 1935 1936 1930 1936 1938 Vincent Stewart Erb Bernhardt Rchlen Gowers Voigt Moeli Berg:er l\Iarina Briand Hillenbere: Leimbach Simerka Thomas FrenKe1 & Foerster Collins !\Iott Sarbo Santonostaso Pires & Canha Lag:rang:e Jaensch Orlando & ChilchilnitsKV Schaeffer & Merie:ot de Treie:nv Schaeffer & Merigot de Treigny DISEASE T GP LC TOTALS 51 20 84 33 35 72 165 - 40 8 78 (16) 16 44 (94) (355) 59 45 /31) 15 336 (15) 70 178.4) 40. 0 (78. 0) 48.4 (45. 7) (61. 1) (57. 0) 71.0 (54. 6) (48. 9) (51. 7) (25. 0) (84. 0) 30.0 (63.1) 77.0 (76. 6) 88.7 50.0 61.4 57.1 (60. 0) 52.1) 90. 9) (98.4) 8 (4) 7 (10) 10 (5. 7) (3.2) (3.6) (20. 0 19. 9\ 32 (17. 8 33 60 (108) (95) 173 (25) 62 12 108 125 30 59 93 2019 66.2% 257 16 500 108 92 60 60 400 52 111 49 140 62 195 50 69 PUPIL REACTio;-.;s dissociatPd immobile imnnired # # # '1o % - 5 11 (31) (60. 0) (15. 3) 19.0 25 41 (16) 18 8 (18) 11 (23.2) (44.6) /26. 7) (30. 0) (2. 0) 34.0 (9. 9) - 40 8 78 (16) 21 :;5 (125) (355) 84 86 (47) 33 344 (33) 81 -!3 62 32 21 130 240 17 8 991 2 - 16 l\ 116 (99) 180 (35) 72 12 140 125 32 59 .-1% 2319 MIOSIS % # (78.4) 40. 0) 78. 0) 48.4 60. 0) 76.4) (76. 0) 71. 0 77.8 (93. 5) (7!:i.3 (55. 0 (86. 0 64.0 (73. 0) (l:l'I. 8 /82. 7\ 79.8 92.3 70. 0 71 3 57.1 77.8 52 1 97 1 (98.4) 23 7 41 (9) 18 (48) (38) (30) 32 39 (18) 24 125 (14) 10 10 63 (30) (34 l (13) 14 7 24 70 10 16 76. 9% 756 % (45. 1) /35. 0) 41. 0) 27.2 51.4) 2/3 23,0 7.0 (29.6) 42.4 30.0 ,10. 0 31.1 26.0 9. 0) (20.4 (45. 0) 49.0 14.7 26.0 13.9 33.3 (13. 3 29.2 30.3 (26. 7) 24.8% ~ 3052 From Loewenfeld, Survey Ophthal. Numbers in brackets= calculated Table 19-5. numbers without brackets given by author. Miosis considered essential in the Argyll Robertson syndrome YEAR AUTHOR 1906 1913 1914 1921 1926 1927 1927 1927 1928 1930 1931 1932 1933 1933 1934 1934 1935 1936 1937 1938 1938 B38 1939 1946 1951 1954 1959 Bach Behr CHIEF " Behr Weisz Boente ra1ter Behr) Lafon (After A. R.) Wilbrand & Behr Stern (after Behr) Engel Bing & Franceschetti (Behr) McGrath Mc Andrews (after Behr) Merritt & Moore Baudoin (after A. R.) Roemheld (after Behr) Behr Jaensch Burki (after Behr\ Kehrer (after Behr) Myerson & Thau Schwarzenberg (after Behr) Strl,lmme Merritt et al Doe:e:art Apter (after Behr) Kyrieleis From Loewenfeld, Survey Ophthal. 962 14(1969):199-299 by us from data given; 14(1969):199-299 REASONS FOR OPINIOK tried to prove lesion located in cervical cord AR pupil is almost always smaller than normal, in contrast to absolutely immobile pupil -- wanted to differentiate miosis more often associated with AR pupil than with immobility differentiated AR (with miosis) from "simple reflex rigidity (without) to ainerentiate "true" from "traumatic pseudo"-AR pupil (no miosis) thoug:nt miotic AR pupil is always syphilitic miosis taken as part ot aetinition (see Behr) thought with narrow definition most cases are syphilitic the narrower the definition the greater the number of syphilitics definition adopted after Behr with miosis and iris atrophy, all cases thought to be svnliilitic with narrow definition, AR thought to be always syphilitic with narroe aenn1t10n, Ali. almost patnognomot1c tor S.YD!llllS with narrow definition, tabes very probable "true" AR (with miosis) thought to be always svohilitic "true" AR (with miosis) thought to occur in tabes only with miosis almost patho2:nomotic for svnhilis with narrow definition thought to be always tabetic "true" AR (with miosis) and "complicated AR" (without) differentiated "complete" AR (with miosis) from "incomplete" (without) differentiated "AR" (with miosis) from 'simplc:i reflex rigiditv"(without) aitterentiatea true AR(with miosis) from "false" (without) with narrow det1n1t10n AR ·n1ie.my spec1nc tor neurosypnu1s dissociation without miosis is found in non-syphilitic conditions AR with miosis thought to be exclusively syphilitic with narrow definition thought to be almost exclusively tabetic 19. Midbrain Syndromes: Argyll Robertson Pupils / 963 Table 19-6. Pupil sizes reported in patients with Argyll Robertson pupils by Behr and by Jaensch PUPIL SIZE i UMBER OF PATIENTS Behr (1921) complete incomplete 3 22 0 13 0 -1 mm 1 - 2 mm "miotic" ----- "medium" 2 - 3 mm 3 -4mm ..J: ------4 - 5 mm 5 - 6 mm "large" Total From Loewenfeld, S~v--9 90 20 ----- 5 ..J: 64 56 ------- 55 17 ------- 0 complete total 1 6 1 23 r--------- 26 19 ~------- ------ Both (1936) incomplete 0 17 ----- 29 13 1 total 3 35 ------- 26 Jaensch ---- 116 39 ---- total 4 58 1------ 171 56 ----- 7 4 0 0 1 0 1 0 4 120 127 53 180 300 Q htha.J.. 14(1969):199-299 Note the strange inconsistency between these authors' opinions and the data they presented; both considered miosis essential for the diagnosis. Behr defined miosis as smaller than 2 mm, and Jaensch as up to . 2.5 mm. The majority of their own cases does not fit this definition. We have no explanation for this contradiction. R L -----------------------i t ....... ~ t .s >.. ..... " "•-~~~~~m~m~mm~m~mmm~~m~~~~m~mm~m~ml tt-+' .............., .............,.............,. ........ ~.......,.......,.......,.......... .......,.......,........, ........................................................... I 1$ ~ 3t-----..------------i1---------------, ~ .!! 2 ~ } ~ ------ __________________ ,,,-------•,,c .,.... ._~=;:;;:;;:::======~~~====----- ........................................................................................................... ................................................... .... I h-T"TT7rrrTTT.....,...h-rm-i-Trn-rn=n'rrrrn-rrmTrr'rrTTTTTirrrTTT"TrTTTrTT"TrTTTrTTTTTTTrrrl ~ Timti Figure 19- l. Clinical appearance of the Argyll Robertson syndrome (diagram). In darkness or dim illumination the pupils are small. They may be unequal or distorted (as the left one shown here). Line 1: Pupils in darkness. Lines 2, 3, and 4: Bright light on the right (R), the left (L), or on both sides, respectively, fails to elicit light reflexes. Line S: The pupils constrict when the patient looks near, and may become very small. i.n. 0.1.fe<:o,id_. Figure 19-2. Bilateral Argyll Robertson syndrome in a patient with syphilis of the central neivous system. The patient, a 59-yearold man, had a syphilitic infection 25 years before examination. Two years later he began to have generalized seizures. At the time of examination his knee and ankle jerks were hyperactive on the left and clonic on the right side. His tongue deviated to the right. Blood and cerebrospinal fluid tests were positive. His pupils were very small and nearly equal, with extremely poor light reflexes on the right side (solid lines) and none on the left. Both pupils constricted briskly when he looked near and redilated promptly when he looked far. Psychosensory reflex dilation (to sound, arrow) was sluggish and inextensive. Comment: These pupils looked completely fixed to light on clinical examination, but the record showed faint contractions of the right pupil. The near-vision contraction was relatively very good but was limited in extent by the tight miosis. (From 0. Lowenstein, Arch. Ophthal., Chicago, 55 [1956]:356; 0 1956, American Medical Association) 964 IV. Pupillary Pathology: Symptomatology a -- yB ,~ -,-::-A '' 7 ::- \ 5- ,,- ___, , ', lig1t Lf!.ht J ,... ,· ~, , ' '. ,--_,_.,., \ \ , ',J,.,_.. lig/:f,_ ... ---,,e_ "( Figure 19-3. Unilateral Argyll Robertson syndrome in a patient with syphilis of the central nervous system. The patient was a 49year-old woman. Her husband, a chronic alcoholic, had infected her with syphilis when she was 24 years old. She had been treated over a 10-year period, and after repeated courses of penicillin, her blood and cerebrospinal fluid tests had become negative. Four months before examination she began to suffer from almost constant pain in her right foot and leg, with episodes of shooting pain that awakened her at night. She had become extremely nervous, easily excited, and depressed. On examination, both ankle jerks were absent and the right knee jerk diminished. She had a zone of increased sensitivity to cold on her back at the level from about T4 to Tl0. Motor functions, including the cranial nerves, were intact, and vision was normal. Her right pupil was much smaller than the left, and was fixed to light (A and 8). It reacted promptly and extensively to near and to far vision (C). It dilated as much as the normal pupil to cocaine (two drops 2%, shown by arrows c in D). After two drops of I% homatropine (arrow H) it dilated better than the normal pupil (in darkness) so that the pupils became equal (E). Comment: This patient had a classic Argyll Robertson syndrome on the right side, while the left pupil was normal. When seen in room light her right pupil looked relatively large because of the absent light reflexes, but in darkness it was much smaller than the normal pupil. (From 0. Lowenstcin,Amer. J. Ophthal., 42, II [1956):105; published with permission from The American Journal of Ophthalmology, The Ophthalmic Publishing Company) ,.,,,, ~, ' =-=-'· C \ ,,_ 5 '- .,, ~ l ___, ,,,, ...:::.:--------- near 1. .,., ,, ...... ,. , I vision ~ ____ ... ,-- - ~ I QISt!~on.ci+ --------------------------D I 7 ...... ' !-! -+ -+ 5 '< 'I /0 1< >O mcn.l.(f:t!.s'-+ B 2S +u .H .. , "O - --------- ~~- 7 ----- 6 -- ·~ -- ,,"" 5 "<inl.(f:t!.s'-+ Tim.t! - 6 5 C-.-----L~-I l I - 4~0-~------:::::---~___ ------=====J..:;;~------=-3 ----i-•.::.."'_-- ___ 1-----11-- ~ t - - FY. ~-----, ____ -----1 NV. - r s'-E--1-1 1----F--1-1-1- 4 3 I_ E ~ - I -----,=-ee..- ~--,_______ ld.r. - r· I FV. ------I I ------=r-----\ .... -:;------=Id.I.--------~ E O. lsec.-+ Figure 19-4. Unilateral light-near dissociation without miosis. The patient, a 46-year-old man, had had a syphilitic infection 7 years before examination. For the last 5 years he had suffered from "knife-like" pains in both upper thighs which lasted about 2 seconds. These lancinating pains were at first infrequent but became steadily worse. Both knee and ankle jerks were absent, but there were no other signs of spinal disease. The blood and cerebrospinal fluid tests were strongly positive. Best vision was 20/20 in each eye despite a binasal field defect that was attributed to opto-chiasmatic syphilitic arachnoiditis. The right pupil (solid lines) was larger than the left (broken lines) and failed to respond to light (A, B, C) and to darkness (E, F). lt constricted almost as well as the left pupil to near vision and redilated promptly when fixation was returned to the far fixation point (D). Comment: In this patient the dissociated pupil was larger in darkness and in light than the pupil that reacted to light, but the near-vision reaction was not tonic. 19. Midbrain Syndromes: Argyll Robertson Pupils / 965 6---~ s- ~--~ t ~ s:! ~ 1--•---1--------1 I___ 2. 1 ~-----=---=_= __=_~J=~,'\-----------1------~ ~'-..!-~- Jt-----1---'-'~ ...... - I 1111111111 111111 I --- ',;-::._::_~-=-:-~;:;;:;:;;:;_;_;:;_~_;:::_::::::::===d.~ ------r ...I.~..._..._________ - •---------•--~ Zr. /2 ...:::----- ',~' '- 11111111111 f. 11111111111 •IIIII n. llllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll 111111111111111111111111 0.1$ec.-+ Figure 19-5. Bilateral incomplete Argyll Robertson syndrome in a patient with syphilitic aortitis. The patient, a 75-year-old man, was found to have syphilitic aortitis at the age of 61. Three years later small pupils with sluggish light reflexes and extensive contractions to near vision were observed. Despite treatment the patient developed severe aortic insufficiency and stenosis. His tendon reflexes were overactive, more in the legs than in the arms. The reactions of the pupils to light were inextcnsive (best response shown in the graph), but during the near-vision effort the pupils constricted promptly to below 2-mm ize, and they redilated briskly when ftxation in the distance was restored. Comment: Under clinical conditions this patient' pupils looked fixed to light, but after dark-adaptation residual light reflexes could be elicited. The near responses were extensive, e pecially in view of the patient's age. (From 0. Lowenstein, Amer. J. Ophthal., 42, II [1956]:105; published with permission from The American Journal of Ophthalmology, ' The Ophthalmic Pub Ii hing ompany) Figure 19-6. Tabo-paresis with asymmetric Argyll Robert on pupils. The patient was a 68-year-old man with a history of syphilitic infection at the age of 26. He had been treated off and on, and his serologic reactions were said to have been negative for many years. During the last 2 year he had increasingly evere headaches, pain in the legs, and difficulty walking. Neurologic examination showed absent ankle and knee jerk and an ataxic gait. There was mental deterioration, with defects of judgment, hallucinations, and paranoid ideas. The pupils were unequal. The light reflexes were almo t lost on the right and reduced on the left side (A, B, C). Both pupils reacted well to near and to far vi ion (D). They dilated fully to cocaine and to homatropine eyedrop (see Figure 19-13). Comment: Considering the patient' age, the nearvision reactions were surprisingly vigorous. The right pupil showed the classic Argyll Robertson syndrome, but on the left ide the light reflexes, though poor, were not abolished. t E E O. lsec.-. Figure 19-7. Fairly large, dissociated pupils. The patient was a 47-year-old man. About 7 years before examination he had fallen from a window on the fifth floor of a building. He woke up in the hospital with a body cast. He was told that he had fractured his first and second lumbar vertebrae. Since that time he had suffered from weakness and numbness of both legs and recurrent pain in his rectum, which radiated down the back of his thighs. The pain were brought on by straining and by climbing stairs. In addition, since the accident he had some incontinence of urine. eurologic examination showed a steppage gait with bilateral foot drop, weakness in both legs, especially in the foot muscles and calves. diminished patellar and absent ankle reflexes, but no pathologic reflexes. Sensations of pain and touch were impaired below the level of TI, and position sense wa poor in both legs. Blood serology was negative, but the spinal fluid was positive for syphilis. The patient had monocular diplopia with his right eye, with best vision 20/40 in the right and 20/15 in the left eye. There was a scar in the t~mporal side of the right cornea. and an opacity in the deep antenor ~ortex of the right lens. The diplopia and reduced acuity in the nght eye were ascribed to this traumatic cataract. There wa '?1arked anisocoria, and both pupils constricted inexten ively to hght, worse on the right side (A and B). Reflex dilation (arrows) was present, and contractions to near vision were more extensive than those to light (C). Redilation after the near-vision effort was prompt. Comment: The patient's near-vision reactions were almost twice as extensive as those to light, but vision was too good to explain this. Neither pupil was tonic. It could not be determined whether the pupillary syndrome was caused by the trauma or by syphilis. 968 I IV. Pupillary Pathology: Symptomatology Table 19-7. Pupillary reflex dilation in patients with Argyll Robertson syndrome YEAR AUTHOR 1864 1865 1868 1869 1 80 1 82 1 83 1 83 1 83 1 84 1 85 1887 1889 1 92 1 92 1 93 1 94 1 96 1 96 1 99 1900 1900 1903 1905 1906 1906 1906 1910 1913 1914 1921 1921 1922 1925 1926 1928 1931 1936 1936 1945 1948 1951 1959 Duchenne Trousseau Radcliffe Arinrll Robertson Erb Moeli Buccola Gowers Lewis Althaus Moeli Moeli Ber11:er Guillerv Kornfeld & Bikeles Knies Krafft-Ebbin11: Lewis Siemer ling Ilirschl Dcicrine llarris Mott Holden Buttino Nadal Posev & !'ffiiller Weiler Doren Deierine STATEME:NT Samaia Behr Bielschowskv Sarno Danis & Co•"nez Ft>instPin Sommer Jaensch Velter Berl!' Roques Doo-o-art Guillaumat From Loewenfeld, Survey Ophthdl. YES miotic oupils in tabes dilated in painful crises verv small pupils in tabcsdilated in oainful crises immobile miotic puoils intabcsdilated in painful crises cited others that miotic pupils in tabes dilated in painful crises Pain dilation is often im12aired in patients with AR nunils pain dilation is often missing in Patients with tabes dilation latent period is prolonged, and dilation sometimes absent nain dilation may be marked 1 even with verv small AR nunils widP dilation to stron11: stimuli and psvchomotor dischar11:es miotic AR nuPils ~ in paroxvsms of nain Pain dilation is "by no mean/ii aJ\:i;:ays missing" nain dilation is absent in manv but good in ,:lOme dilation to nain may be Qresent in tabetic AR nunils in nainful crises miotic AR pupils often dilate nain dilation mav be found insnite of 1-,,~nln•esia AR nunils dilate to sensory stimuli -- mav be lost in late st>iP-e AR nunils usually do not dilate to sensorv stimuli dilation reflex is lost in about •13 % of tabctic AR nunils pain dilation is often reduced nain dilation may be extensive in miotic AR nunils in tabes pain dilation is 11,·enerallv lost nain dilation mav be absent Qr Qresent with ninpoint PUPils oain dilation mav be absent as a rule sensory reflex is absent found nain dilation absent only in 1 of 70 cases some AR ounils react well to oain stimuli nain dilation mav or may not be lost >Jain dilation was absent in 46% of 173 cases sensorv dilation was lost in AR pupil nain dilation is generally lost •Jain dilation is not always abolished in miotic AR puoils sensorv dilation is always disturbed or absent senso~ reflexes are lllii!.lii!llyabsent natient with AR oupils ;i;cacted :i:i::elJ to sensorv stimuli nain dilation is lost early in AR syndrome an1.ono- 7 naticnts oain dilation was absent 5x !,;!resent 2x AR l)unils dilate to changes of pressure in ear canal sensorv dilation is almost alway/ii JQiiltin marked AR syndrome typically, reflex dilation is poor nain dilation is more or less regularly a!;!sent in older cases oain dilation is not always absent in AR pupils oain stimuli may cause mydriasis in AR oupils pain dilation is not alwa:z:s lost in AR pupils NO + + + + H /-\ (+\ + + + + + + + + + (-\· - + /-\ + + (-) + + + + + - + - + + (-) (-) + + + 14(1969):199-299 stdtement thdt dildtion is present, dt ledst in some pdtients stdtement thdt it is not present; (-) = qudlified stdtement, stdtements dre not entirely Cdtegoric). Sommer, 1944). And once the definition was thus limited, it is not surprising that the number of Argyll Robertson cases with active reflex dilation began to decline sharply: whenever the dilation was observed, it was said that the patient did not have Argyll Robertson pupils. It has been our experience that pupillary reflex dilation may indeed be absent or reduced in patients with the Argyll Robertson syndrome. But this certainly is not the rule, and in many of these patients reflex dilation is prompt and extensive. Further, there is no fixed relation between the miosis and impairment of reflex dilation: since each of these signs may be present without the other, there could be no causal relation between them. And in patients with unequal pupils, the smaller may dilate as well or even better than the larger (Figure 19-10). with AR pupils; mainly negdtive - = more or less distinct (note thdt most negdtive 6. Bilateral, Unilateral, and Asymmetric Syndromes The Argyll Robertson syndrome is bilateral in most patients, although strictly unilateral cases do occur (see, for example Figure 19-3). These are so uncommon that for several decades after Argyll Robertson's papers individual case reports were published as rarities. The importance of the unilateral syndrome therefore does not derive from the number of patients involved but from the fact that its existence limits the choice of anatomic sites that can be considered for the responsible lesion (see below). In some cases the two pupils are alike in size and in reactions. More often they are asymmetric: one pupil may be larger than the other, or their shape may differ; the residual light responses or the near-vision contractions may be more extensive in one than in the other eye; 19. Midbrain Syndromes: Argyll Robertson Pupils or an Argyll Robertson syndrome on one side may be associated with complete or incomplete rigidity of the other pupil. The frequent occurrence of such combinations emphasizes the futility of trying to construct a division between the Argyll Robertson pupil and immobile, miotic pupils. 7. Iris Changes It was known before Argyll Robertson's time that syphilitic iritis could result in contraction of the pupil and c;hanges in its shape. Iris pathology then would render the pupil immobile to light. Such damage has been described often. In 1905 Dupuy Dutemps published a paper, "On a Special Form of Iris Atrophy in the Course ofTabes and General Paresis," which attracted a great deal of attention and has been cited many times since by DupuyDutemps himself and others (Table 19-8). He had observed in patients with the Argyll Robertson syndrome-and only in these-a reduction, sometimes diffuse and sometimes in sectors, of the pleats and the relief of the iris, which therefore "lost its brilliant shimmer." In cases with sector atrophy the pupil was distorted: the pupil segment corresponding to the damaged part of the iris was larger than the rest, and it contracted more sluggishly. There was no inflammation, and the light reflex was always lost before appreciable atrophy could be seen. Behr's description differed: he said the healthiest iris portions had the largest pupil segments, and in general iris pathology was mo t marked in eyes with the smallest pupils. In fact, Behr believed the damage to be caused by continuous miosi : the iris looked "overstretched": the 61--__- --- -+·'·--__-+-+_-_-_-_-_-_-_-_-_-_-_-_-----_-_-_i_-_-_-_i_l-_-::J..,~l...--c---...,•i"'=e--i-' _______ ---i -------- - ---- E' 11. 969 radial trabeculae appeared thin, and the fine connecti~g strands between them, which in normal eyes ran m various directions, could no longer be made out; the crypts no longer could be seen, and the iris l?,o_ked!a_de~; the stroma seemed flattened and its surface s1mphfied, as if its intricately interwoven strands had been combed straight. Several later workers have given the same account with minor variations. The question arises, however, as to whether this appearance of the iris was due to structural damage. Long-term, marked miosis, brought about by drug treatment, has sometimes led to iris cysts but has not resulted in iris damage as described by Behr. Furthermore, Behr's descriptions fit exactly the picture of a normal iris with the pupil constricted by miotic drugs (Figure 19-11): the stroma appears flattened, the crypts narrowed, the trabeculae pulled out straight, and the design simplified. Moreover, these changes in iris detail during miosis are much more visible in light eyes with many crypts in the anterior stroma than in smooth-surfaced, dark ones-again exactly as was described by Behr for the Argyll Robertson syndrome. In some cases defects of the posterior iris layers were found. As these involved the posterior pigment, they were especially obvious on transillumination of the globe. Local patches of discoloration, pigment deposits, and pits in the anterior iris surface also have been mentioned. In some cases such damage followed yphilitic iritis, uveitis, or choroiditis; in others it came on gradually over months or years without a known inflammatory episode. It has been said that iris damage is present in all eyes with the Argyll Robertson syndrome. This is, however, ~1----1----1----B--------t--~-i-+----:!=5=' t3 p I ---- ---- 7ll. ,,,,.---'I, __ _______ __j ~ ,.,:./_-t---t--------J ll. O.l$t!C.-+ Figure 19-10. Extensive p ycho ensory dilations in two patients with Argyll Robert on pupil . A: The patient was a 36-year-old man with congenital syphilis, treated at the age of 8. He had a saddle no e with perforated septum and bilateral optic atrophy. Be t vision was 20/200 on the right and /200 on the left side. At the time of examination the blood and cerebrospinal fluid tests were negative. Both pupils were small for the patient's age and showed poor light reflexe . These did not, however, have "low-intensity" form. The near-vision contraction (not shown) were prompt and extensive. P ychosensory reflex dilation in re pon e to a sudden sound stimulus (arrow) was good. 8: The patient wa a 41-yearold woman. Five years before examination he had an acute infectious disease of unknown nature, with somnolence and 104°F fever for several days, followed, upon recovery, by headaches, restlessness during the night and sleepine during the day, irrita- bility and depression. These signs gradually became milder but did not subside. _Neurologic, serologic, and cerebrospinaJ fluid tests were negative except for hyperactive, slightly asymmetric deep tendon reflexe_s.The patient had right exotropia, said to have been _present smce early childhood. Both pupils were fixed to light but did con_tractto near vision (not shown). ln response to a sudden sound stimulus, the small pupil dilated more extensively th~n t~e la~ge one. c_ommelll: Both these cases showed that mi011c,_ d1ssoc1atedpu~1ls can dilate very well to psychosensory stimul~t'.on. In both pat1~nts the pupils also enlarged upon local adm1~1strat1onof_cocam_e(2~ ); and after this dilation the nearv1s1onc~ntractJon gamed m_amplitude (because of the improved mechanical r~nge), but the light reflexes remained absent. (From 0. Lo~enstem,_Arch. Opltthal., Chicago, 55 [ I 956]:356· c 1956 Amencan Medical Association) ' ' 970 IV. Pupillary Pathology:Symptomatology Table 19-8. Iris damage in syphilitic Argyll Robertson syndrome iris damage iris damage YEAR "O <ll AUTHOR .0 ·;:; " Ill <ll "O 1901 1902 1902 1905 1906 1906 1909 1910 1911 1912 1912 1913 1918 1918 1921 1922 1923 '1923 1923 1924 1924 1924 1925 1925 1926 1926 1927 1927 1921 1928 Levinsohn & Arndt Hirschberg Tcrson Duou'<-Dutcrnps Nadal Sgrosso Lafon Jackson Bumke Magitot Winavcr Behr Bollack l\lagitot Sarnaja Mosso Barkan Duverger & Redslob Redslob"' Duouv-Dutemos Lodato Vuillaume Behr Duouv-Dutcmns *"' Mawas * Sabbadini Dupuy.Du temps Redslob Santonostaso Bollack From Loewenfeld, rlote: Survey Ophthal. "O "O "8::, " ·;:: AUTHOR .0 + + + + + + + + + + + + + + + + + + + + + " 8 ::, 1/l <ll " ol "O ol + + + + + + + + "O '-' 1/l Ill 1/l + ~ YEAR 192 192b 1929 1931 1931 1932 1933 1933 1935 1936 1936 1936 1936 1938 1938 1938 1938 1939 1942 1943 1946 1947 1947 19-±7 1948 1950 1954 Kaminskaja Pavlova Ticri Dupuy-Duternps Kvrielcis Vancea Ille Grath Fillipp i-Gabardi Tille Behr Jaensch Orlando Schaeffer & lllerigot de Trei,rnv Tomey Bona Bollack Guill au mat & al Rea Schaeffer & Mcrigot de Treie:ny Adrogue Velter Berg Vidal & Brodsk"V Cordier & Passavin * Kissel R, ol * Walsh Cordier & Pass av in * Poos Apter + + + + + + + + + + + + + + + + + + + -+ + + + + + + + 14(1969):199-299 This table contains only publications with iris damage discussed mechanism of the Argyll Robertson syndrome. • • herpetic iris damage; ** = traumatic iris damage. in relation to the 113 Figure 19-11. Segment of a normal iris with the pupil large (A) and constricted (B). (From I.E. Loewenfeld, Survey Ophthal., 14 [1969]:199) 971 19. Midbrain Syndromes: Argyll Robertson Pupils erroneous: while iris damage is not rare among these patients, it certainly is not a constant feature. 8. Phenomena Discussed in Connection with the Argyll Robertson Syndrome Three phenomena have played a role in the discussions about Argyll Robertson pupils: first, the "lid-close response," which was often still present when the light reflexes were entirely abolished; second, "paradoxical reactions to light," which were said to occur in this group of patients only; and third, the so-called "perverse reaction to near vision." These three phenomena are discussed in separate sections and need not be considered here. The same is true for the "inverse Argyll Robertson syndrome" (see Chapter 21). 9. Reactions to Drugs Argyll Robertson had said that in his patients strong solutions of atropine "induced only a medium dilation" of the pupils, and this statement has been repeated many times since. Those wishing to restrict the eponym in the interest of the syndrome's being "pathognomonic for neurosyphilis" included impaired reactions to atropine in their definitions. As often happens in subjects discussed for a long time, these drug reactions shriveled in the course of years from "imperfect" to "poor" and R L 1- 2- 6 thence to "absent"; and finally these pupils were said to "fail to respond to mydriatic drugs." But, as general statements, all of these descriptions, including that of Argyll Robertson himself, are erroneous. While in some patients with the syndrome the pupils indeed react poorly to mydriatic drugs, many others react with prompt and extensive dilations to atropine and to cocaine (Figures 19-12 to 19-14 and Tables 19-9 and 19-10). The general statements in this matter, unsupported by experiment, simply do not agree with the results of examinations done on actual patients (Figure 19-15). In all patients in whom we have tested these reactions (in darkness), the pupillary dilation to cocaine was less marked than the reactions to atropine or homatropine, while the opposite is true in normal subjects. This difference is of theoretical importance (see below and Chapter 14). In the past it has been remarked that those Argyll Robertson pupils which have poor reactions to mydriatic drugs also tend to constrict poorly to miotics, and that their responses to physiologic stimuli are reduced to a similar degree. This has been our experience also. Since nothing seems to produce a response in these pupils it appears reasonable to think that the effector muscles must have been damaged by the disease process. Sometimes Argyll Robertson pupils were observed to constrict to instillations of 2.5% mecholyl, and some authors have concluded that they are hypersensitive to cholinergic stimulation, which would explain the miosis. This, however, is far from a constant feature, and is easily explained by the common occurrence of corneal damage in these patients. -c,-ci-c,i: ____________________ 5 ------------- ~ If 3 i 3- -et-ct-ls 0 ID IS ----- >D lS :-- ,--l--------- 4- 3 i >--Af_i\f 0 mu1 ..... Figure 19-12. Reactions to instilled drugs in unilateral Argyll Robertson syndrome (diagram). The right eye (R) is shown as control, with drugs assumed to be instilled bilaterally. Line l: The Argyll Robertson pupil is smaller than the normal puil in darkness. Line 2: It dilates up to normal size when atropine-like drugs are in tilled: the normal pupil does not dilate much because its sphincter muscle is relaxed in darkness, but that of the Argyll Robertson pupil is not. Line 3: Cocaine also dilates the Argyll Robertson pupil, but it remains smaller than the normal pupil because it's sphincter muscle is spastic. In darkness the normal pupil does not have this problem. Line 4: Both pupils contract well to miotics like pilocarpine or eserine. s 10 IS >o - - A~- JS 30 •o 35 30 7 A ---- .. ♦S 50 n 60 ss 60 _,. - "" 55 ~ Figure 19-13. Pupillary dilations to cocaine and to homatropine in the patient shown in Figure 19-6. Top line: Three drops of 2% cocaine hydrochloride were instilled into each eye (each drop marked by arrow c). Bottom line: Two drops of L% homatropine hydrobromide were given (arrows A). The tests were done in darkness. The pupils reacted well to both drugs, with the small one (with complete Argyll Robertson syndrome) more so than the larger one (with residual light reflexes). (From 0. Lowenstein, Arch. Ophthal., Chicago, 55 [ I 956 ]:356; 0 1956, American Medical Association) 972 IV. Pupillary Pathology: Symptomatology Table 19-9. YEAR Reactions to instilled cocaine in Argyll Robertson pupils A .THOR 0) PUPIL REACTIO '8 TO COCAINE (authors' words as far as possible) > '-' <'$ :;:l 0) :... 1 :R'S 1 :87 1 :as 1 92 1 93 1 94 1900 1901 1902 1903 1903 1905 1905 190G 1908 1909 f---lilQ_ 1911 1912 1920 1920 1921 1923 1922 1922 1923 1923 1923 1923 1923 1924 1926 1927 1927 1927 1938 1938 1939 1948 195G TThthnrf Moeli Heddaeus Guillerv Knies Jackson Levinsohn Arndt Terson Bach Lcvinsohn Grasset Levinsohn Ferrier Levinsohn Cantonnet& Touchard Jackson Bumke WinaverLandolt Trantas Samaia Behr BinswanP-cr Redlieh Brannvcll Laie-ncl - Lavas tine Llovd Rowland Bramwell Rowland & Skirball Danis & Coppez Boente Lafon Revs Cimbal & Schaltenbrand Pevret Romberg Hoaues & al Cogan From Loewenfeld, +=positive Survey statement; 0phthal. dilated in AR nunils failed in Horner's never failed in AR punils dilated in AR pupils dilated in AR pupils, failed in Horner's dilated in AR oupils dilated in AR' as in the normal state" dilated prom11tlv in AR pupils 37 cases AR pupils all dilated rlid not work I in case with iris atro nvJ dilated in AR pupils dilated in AR pupils ctilatect in AR pupils r-eactect well in AR ounils enlarged in AR nuoils as in normal worked well in AR pupils small AR pupils reacted less, as well, or more than lance ones dilated in AR pupils dilated in AR pupils dilated in AR ounils reacted inextensively in AR pupils dilatca in AR pupils AR pup11s rcacum normally aiiatect very quickly in AR pupils e111atcct in AR pupils worked well in AR punils 1 patient with AR puoils failed to react AR puoils reacted dilation was intact in AR pupils rlil ated in AR ouoils dilated in AR ounils 22 cases -- all dilated within 35 minutes dilation fails in AR puoils (general statement) reduced reaction in "true ' AR pupils reduced dilation (general statement) dilated in AR pupils dilated in AR pupils "O 0 '-' :::, "O 0) :... + + + + + + + + + + + + + + + + + + (·) + .,. + + + + + + + + - H () + + hyposensitive to 0. 25% cocaine tabetlcs wnn A tt: pun s reactca max1m. ctilate<l in AR pupils ctilation reduced as m Horner s syndrome !S4 .,. (-) + (-) 14(1969):199-299 - = negative statement; Figure 19-14. Reactions to cocaine and to homatropine in a normal man (A) and in a patient with Argyll Robertson syndrome (B). A was a healthy 24-year-old man, and B a 67-year-old man with meningo-vascular syphilis. B had bilateral optic atrophy, with best vision 20/70 in the right and hand movements in the left eye. His miotic pupils were distorted and fixed to light, but they constricted to near vision. Two experiments were done with each individual, 3 weeks apart. The room was in darkness throughout. In the normal subject the left eye only was treated (broken lines), leaving the right pupil as control (solid lines). In the patient the (-) partly negative statement. drops were placed into both eyes. At each arrow C, one drop of 2% cocaine hydrochloride was given, and at each arrow H, one drop of I% homatropine hydrobromide. In the normal subject cocaine caused faster and more complete dilation than homatropine. In the patient (B) the pupils were smaller in darkness, and they enlarged more extensively to homatropine than to cocaine. The homatropine-induced dilation was more extensive than homatropine-enlargement in the normal subject. (From 0. Lowenstein, Arch. Ophthal., Chicago, 55 [1956]:356; 0 1956, American Medical Association) 19. Midbrain Syndromes: Argyll Robertson Pupils Table 19-10. Reactions to atropine in Argyll Robertson pupils YEAR AliTIIOR 1846 Gerold Billod Duchenne Stell wag Trousseau Leidcsdorf .. Lins tow Trousseau IUnecker Robertson Robct"tson Russell Leber Dubos 11:363 lb64 1864 1865 1,67 1,(>7 hG7 lb6b 1869 lb70 lb70 lb72 lb7'! ., lb7'! lb76 1876 187" l ':Ht-lb79 lH!->0 B81 1 ,bl 1383 1385 lb93 189b 1900 1900 " # CASES 1 case 1 case 1 case cases , - - 5 cases cases case case case 23 cases 11 cases II :\lobcchc Ilempcl Doutrcbentc 1 case Fo·✓ ille Galezowsky Stewart EdJ P icrcl' hou_\· Wcrnicke l\lobius Landes be nr Oliver Schmidt-Rimplcr llarris Levinsohn " 1 case cases 1 case 13 cases 1 case - - Levinsolrn l~0~ ·1erson Toulouse & Vurpas Xadal Posey & Spiller Lafon Behr Suchy Santonoccto S:m1aja 11 From Loewenfeld, &Arndt " Survey " 2 1 1 1 1901 1903 190G 1906 1900 1911 1917 1920 1921 / 1 case cases 9 cases 28 cases cases cases - cases 1 case G cases 17 cases II Ophthdl. RATED TATEl\IE?\T ++ ++ dilated dilated die! not dilate mav fail to dilate pinpoint pupils sornetimes fail to dilate never saw miotic l)upil fail to dilate dilate normally clllatcct dilate l)Oorly less than normal medium dilation, same statement same cases. good dilation maximal dilation reacted lai[C(I to tlil::l.le dilated promptly medium dilation rccluccc.J actwn pinpoint pupils UL'C atropine resistant full dilation pinpoint for years, moderate dilation always dilated, though L·educed rniotic pupils dilate quickly pinpoint puplls ctLlated dilated, though less than normal incomplete dilation hyporeact in late tabes long I as ting clilation tiny pupils with partial ctilatLOn maximal dilation dilated ,·cry extensively dilation in all suqJrisingly - - ++ ++ ++ + +(+) +(+) ++I+++ ++ +++ 1-(+) +(1-) +++ +(+) +(+) +++ ++ +(+) +(+) +(+) 1-++ +(+) I-++ +++ +++ ++ + +++ +++ +(+) +(+) ++ ++ +++ ++ +(+) energetic poor ctllatwns, Clue to ins atroph_v dilation longer lasting than normal pro longed dilation incomplete dilation less than normal dilatca dilated all rcactecl well 13 nonnal 2 pinpoint pupils limited 14( 1969): 199-299 Figure 19-15. Reactions to instilled atropine in Argyll Robertson pupils (see individual statements in Table 19-10). The solid line represents findings in 357 patients described by various authors (same as in Table 19-10); the broken line shows 17 descriptions of patients, with the number of cases not identified (each more than 1 but counted as 1); and the dotted line refers to 33 general statements not based on actual observations. The ordinate shows percentage of patients or of reports, respectively, in each group. The symbols on the abscissa (same as in Table 19-10) correspond to descriptions of the atropine responses, as follows: - , no dilation; +, poor, inextensive, slow, limited, moderate dilation; +(+),medium, incomplete, less than normal, reduced dilation; + +, normal dilation;+++, good, extensive, fast, prolonged, prompt, maximal dilation. It will be seen that the groups dealing with actual patients followed the same trend, almost diametrically opposed to unsupported general statements. (From I.E. Loewenfeld, Survey Ophtha/., 14 [1969):199) cm! 50 f I 40 ;30 l l t -L_ 20 10 0 ...,~------~:;,==$---,------,--+ +(+) .....--++ +++ 973 Table 19-10. YEAR (continued) AUTHOR 1922 1922 1923 1923 1924 1924 1!/ CASES - Redlich Wilbrand & Saenger Boehning Rowland Bramwell Jludovernig II cases "series" - 2 cases II 1924 1925 1926 1927 1927 1930 1931 1931 1932 1933 1933 1934 1934 1933 tabes 22 cases Rowland & Skirball Behr Danis & Coooez Boente Lafon Engel Adie Bing l\Ic Grath l\Ic Andrews l\lerritt & l\loore Editorial. J. Al\1A Schaeffer Lagrange & Lagrange II cases cases cases - cases 21 cases 11 1933 II Sandor 11 II II 11 1936 193G 20 cases 11 II Kanovama Orlando & Chilc.:hilnitsky Schaeffer & l\lerigot de Treigny l\leyerson & fhau Schaeffer & .i\Tcrigot de Treig11y 1936 193t> 193':> II cases many 27 cases cases 32 cases 11 II 1938 1939 1947 1948 1951 1951 1956 1957 1958 1959 1961 1963 - Veltcr Romberg Walsh Rouques &al Bonnet Doggart Cogan Pietrushka Sorsby Guillaurnat & al Huber Clayton 4 A_!.-, 81 cases 1 case - 1 case - 1 case r-- -------3 -d_-1--r--------- T-z-2 -:-I1. r • a2 4 __ I ___ 3 2~ t 1 1 I I 1. r. ------------------- - IN. V. ! ,=r--=----,=+---- 2(1) 1 h.r.l ~ ; B2 ___ i-----ii i I"'-1 OF.V.lN.V. ;::l 0. time 974 in 0 .1 sec._. I ~F.V. I 5 Bl s 4~0---=-2 s .s ,., _!_____________ ---- 11.r.l ------------------ II___ _.,,.-F.V. I I STATEMENT dilated poor dilation dilated dilated poor dilation dilated dilated dilated well within 28 minutes poor dilation as part of definition poor dilation as part of definition poor dilation as part of definition poor and slow dilation poor dilation as part of definition poor dilation as part of definition rnav react verv well slow, inextensive and long-lasting poor dilation as part of definition poor dilation as part of definition poor dilation as part of definition mvdriasis is not alwavs noor only one poor the rest good two poor 11 medium 7 maximal m·erage dilation 7 .1 mm., 17. 2 days atropine dilation normal 9 normal lo extensive, but less than normal somewhat slower, but as long as normal 13 !!OOd 19 normal 18 incomplete "t.vpically" poor dilated to homatrop ine slower, somewhat longer than normal dilated widely poor dilation as part of definition dilat10n as part oi definition r.o dilation 'reduced as in Horner's" dilated dilate more slowly than normal not always poor dilation do not dilate dilated well ' I RATED ++ + ++ ++ + ++ ++ +++ + + + + + + +++ +(+) + + + ++ + +++ + +(+) +++ +++ I ++ ++ +(+) +(+) TTT ++ +(+) + ++ +(+) +++ + +(+) ++ +(+) ++ +++ Figure 19-16. Stability of the Argyll Robertson syndrome over a I 0-year period. The patient was first seen at the age of 53 because of her pupillary syndrome, which had been discovered accidentally. She had no complaints, and there was no known history of syphilis. Neurologic, ophthalmologic, serologic, and cerebrospinal fluid tests were all negative. She could not tell how long her pupils had been abnormal. Both pupils were small and reacted only minimally to light (A'). The smaller right pupil contracted vigorously to near vision and became quite tiny (solid line in A2), while in the left eye the near-vision reaction was impaired, although it was more extensive than the best light reflexes (broken line in A2 ). Redilation after the near-vision effort was prompt on both sides. Ten years later the patient was seen again. She had been well except that each time she went to have her glasses checked, her pupils were noticed, and she was again examined extensively at four different hospitals, all with negative results. These repeated examinations had made her very worried about her condition. It can be seen that the pupillary syndrome had remained entirely unchanged, except that her pupils had become slightly smaller, as would be expected over a IO-year span (B' and 8 2). (From I.E. Loewenfeld, Survey Ophthal., 14 [1969]:199) 19. Midbrain Syndromes: Argyll Robertson Pupils 10. Accommodation In the classic Argyll Robertson syndrome accommodation is not affected. Since it is often distrubed in dissociated pupil syndromes caused by damage to the oculomotor nerve, the ciliary ganglion, and the short ciliary nerves, the integrity of accommodation in the Argyll Robertson syndrome has diagnostic value and theoretical importance. When the oculomotor nerve is damaged in later stages of the disease process, the miotic Argyll Robertson pupil may enlarge and become fixed, and accommodation may become paralyzed. 11. Clinical Course In typical syphilitic cases the course of the pupillary syndrome varied. Since it did not impair vision or cause pain, it could go unnoticed for many years, especially in patients with dark eyes. Even in "pupil-conscious" eye or syphilis clinics, the early stages, with only slight slowing and diminished amplitude of the reflexes, often escaped detection. It was thus not uncommon that the full-blown syndrome was discovered suddenly and erroneously tended to indicate a rapid course. In most cases, however, the course is slowly progressive: unless influenced by effective treatment, a gradual worsening of the reflexes up to their extinction appears to be the usual development. This progress may be symmetric or more marked in one eye, than in the other; it may be steady or uneven, with periods of apparent stability interposed between phases of deterioration. / 975 The Argyll Robertson syndrome often was found early in the course of the disease, or it could appear up to decades after the infection. At any time in its development it could be halted in its progress and remain entirely unchanged for many years, as the sole sign of an arrested disease process (Figure 19-16). [n other cases-depending on the general course of the disease-it would go on to miotic immobility, to mydriatic iridoplegia, internal ophthalmoplegia, or total syphilitic ophthalmoplegia. It has been said occasionally that the syndrome may improve, and this may happen to some degree, at least in its initial stages (see Table 19-11). But the fully established syndrome has never been seen to disappear. Reports on "intermittent Argyll Robertson syndromes" pertained to patients in whom the pupils became fixed to light during excitement or painful crises, only to respond again when the patient had calmed down or when the paroxysm of pain had passed. This kind of inhibition of the light reflex by strong emotional or sensory stimuli i , however, normal (see Chapter 10), and it has nothing to do with an intermittent exacerbation of the reflex iridoplegia. In patients with light-near dissociation due to tumors, and caused by pressure rather than invasion, the light reflex may be recovered after surgery. Other patients have been described in whom Argyll Robertson pupils developed upon recovery from an earlier stage of iridoplegia or internal ophthalmoplegia. These cases, also, are misinterpreted phenomena of a different nature (see Chapters 23 and 24). D. Etiology 1. Syphilis The majority of patients with Argyll Robertson pupils had tabes dorsalis, general paresis, or lues cerebri. This was found so consistently, and was drummed into the consciousness of newer generations with such emphasis, that by the turn of the century, when the syphilitic cause of these diseases had become generally recognized, the pupillary syndrome was regarded by many as an unfailing sign of neurosyphilis: its presence ruled out any other diagnosis (Table 19-12). Against this majority opinion cases were presented again and again with "nonsyphilitic Argyll Robertson pupils." These patients either suffered from other diseases or were apparently not ill at all, and congenital or acquired syphilis had been excluded with the utmost meticulousness. Despite this lack of evidence for a specific infection, the patients had to continue under the cloud of suspicion because it was well known that Argyll Robertson pupils could precede the final outbreak of syphilitic diseases of the central nervous system by many years. The numerical probability spoke so much against a nonsyphilitic cause, and the possible consequences of untreated neurosyphilis were so disastrous, that few physicians dared to ignore the warning of this pupillary syndrome. But in the absence of any corroborating evidence whatever, the possible harm caused by the treatments then available, and the evil shadow thrown upon the patient's life, the diagnosis often was made with a heavy heart. After cytologic and immunologic tests for blood and spinal fluid became available, syphilis could be ruled out with greater confidence, and in some patients with nonsyphilitic conditions the time of onset of the Argyll Robertson phenomenon and the course and other details of the disease made it seem indeed farfetched to deny the apparent connection with the patient's presenting illness, and useless to continue searching for the remote possibility of syphilis. 2. Nonspecific Infections of the Nervous System Shortly after the Argyll Robertson syndrome had lost some of its diagnostic importance for syphilitic diseases of the central nervous system (Since more specific serologic tests were available), interest in the syndrome was renewed because it and related pupillary anomalies were found in cases with encephalitis. In fact, for a number of years the subject of encephalitis dominated clinical pupil reports. And no wonder: soon after the first cases had been described by van Economo in 1915, the awful epidemics of lethargic encephalitis swept the globe. This new disease-reminiscent of earlier epidemics of encephalitis with somnolence, but never encoun- 976 I IV. Pupillary Pathology: Symptomatology Table 19-11. Argyll Robertson syndrome exacerbating and improving YEAR AUTHOR REACTIONS TO LIGHT 1882 1883 1 85 1185 1 98 1 98 1899 1901 1903 1904 1904 1906 1906 1906 1907 1908 Moeli Rumpf Landesberg Uhthoff Eichhorst Treupel Tanzi Mantoux Camus & Chiary Bach Jonroy Ferrier Levinsohn Pilcz Pilcz Abelsdorff 1910 1911 1912 1912 1912 1913 1919 1924 1925 1927 Rodiet & Pansier Bumke Ballet & Gallais Goldflam Rose Zaun Jelliife & Waite Duvenrer Kalk Redslob l::i;su Clari< Ohyama Schreiber Clark Jaensch Morax de Seze & al Lowenstein Zeligs & Joseph Walsh Pines Jaffe can be lost and regained in tabes improved on electric treatment variable course (exacerbations and remissions) "traumatic AR" may improve with time *1 may improve though general condition worsens same opinion as Eichhorst immobile during periods of excitement only (GP) *2 1mmooile during; gastric crises onlv "'2 immobile during gastric crises *2 may develop from internal ophthalmoplegia *1 improve during rem1ss10ns may develop from iridoolegia' "'1 may develop from iridoplegia "'1 periodic Alt improved with general condition developed from post-trauma or post-herpes iridonlec:ia "'1 improved and worsened with general condition may improve in remission sudden onset, disappeared in remission developed from internal ophthalmopleg;ia *l developed from internal ophthalmoplegia "'1 AR disappeared in remission (treated) may improve with general condition regained (reduced) light reflex immobile in painful crises *2 small up and down changes superimposed on slower deterioration improved after malaria treatment improved after malaria treatment sudden onset, disappeared on typhoid therapy unproved atter malaria treatment non-syphilitic AR (encephalitis, tumor, vascular) may regress, syphilitic AR not improved after treatment earlv cases may improve (on treatment) improvement after penicillin therapy saw two patients improve on malaria therapy improved on treatment some improvement on treatment 1933 1933 1934 1936 1937 1938 1942 1945 1947 1952 1953 } From Loewenfeld, Survey Ophthal. 14(1969):199-299 *l almost certainly faulty regeneration after third nerve lesion. *2 = inhibition of light reflex by supranuclear mechanism. tered on so large a scale-sprang up in city after city and involved thousands of patients. The rates of death and of permanent disability were frightening, and there was no cure. Among the many variable ocular signs in epidemic encephalitis, Argyll Robertson pupils were described (see Table 19-13). They were typical in appearance, and in all of them the timing and other circumstances, as well as negative serologic tests, made it certain that the syndrome was indeed nonsyphilitic, caused by the encephalitis alone. Argyll Robertson pupils were found occasionally also in patients suffering from other kinds of encephalitis, such as herpes and other virus encephalitis. It was, of course, sometimes difficult to be sure that the pupil syndrome was in fact due to a bout of encephalitis that the patient may have had some time before. But when the onset of the pupil pathology was related in time to the disease, and when blood and spinal fluid tests were consistently negative, it did not seem reasonable to deny a connection between the infection and the Argyll Robertson syndrome, especially since these diseases are known to be able to affect the rostral brainstem. 3. Diabetes Mellitus Before the discovery of insulin, severe cases of diabetes with extensive neuropathy were not rare, and some of them resembled tabes so closely that they were named "diabetic pseudotabes": there were the same shooting pains, the same areflexia, the same paresthesias, anesthesias, motor weakness and vascular defects, the trophic ulcers and Charcotjoints, the involvement of vesicular and anal sphincters, impotence, mental signs and-important in the differential diagnosis-Argyll Robertson pupils. Could all of these defects be caused by diabetes alone, or were these cases perhaps compli- 19. Midbrain Syndromes: Argyll Robertson Table 19-12. The importance of Argyll Robertson syndrome in tabes (T), general paresis (GP), and Ines cerebri (L) YEAR 1853 1867 1872 1877 1878 1878 1878 1&78 1879 1 rm 1 79 1 79 1181 1883 1883 1883 1884 1884 1885 1885 1885 188G 188~) 1889 1891 1892 1892 1893 1893 1894 1894 1 93 1 9G 1 9G 1 96 1 97 1897 1897 1897 1898 1 98 1 98 1 98 1 99 1900 1900 1900 1900 1900 1900 1901 1901 1901 1902 1902 1902 1902 AUTHOR STATE1IENT Seifert von Linstow Leber Forster Erb Foville Galezowski Seguin Erb Gesenms Mobius de Wecker !Iirschber,,. Buzzard Gowers Jackson Althaus Berger Moeli OPPenheim Uhthoff 8iemerling Alexander Mauthner Schiitz Charcot Ra_ymand Grosz Knies BinS\\·ang·er Krafft-Ebbing llirschl l\1ocli Onnenheim Thomsen Brw1s iris as "barometer of disease" one of chief signs (miosis) in all cases diagnostic very common, diaffnostic "most commonlv" "most important" ocular si1m diaffnostic "verv nrominent" "rare in non-tabetic" (except GP) most often" found "crucial", "suffices" for diai:mosis "suffices" for dia1mosis diaQ"nostic diagnostic same in tabes and Q'eneral paresis "almost only" in diagnostic "decisive for diagnosis Yery common diagnostic only in tabes and 12:eneral oaresis majority have Argyll Robertson pupils orten niso1ated physical sign" syphilis is 't)rin1e cause ' "very co1nmon" "in tabes and general paresis onlv" "in tabes and general paresis only" "only obiecti\·e sien" "rare except" in tabes or general par. 'physical sie·n of" tabes or GP "allows hardly other conclusion" common sign diagnostic for brain syphilis diagnostic, may be 'sole sign" most have or will l!'et, GP "a symptom of" neurosyphilis v Go1tti¥gfflhaier :\1oebius Thomsen Abel Gauoo Leszynsky Preston Babisnki & & Charpentier Beevor Deierine Erb Gowers Harris l\lig11ot l\1ott Binswang·er Bonar Babinski Cestan Dufour :\1ann "most constant sii:1.11" "extremely rare except in" Tor GP "almost aII 11 tabes or general paresis ffoccurs onlv in" "occurs only in" 11 12:enerally" syPhiliiic "oracticallv onlr in" "pathognomonic for syphilis" From Loewenfeld, Survey Ophthal. ABOUT SYNDROl\IE "nroof of'' tabes or 2:eneral naresis "onlv in" isolated AR pro\·es "diagnostic for" "almost certain sirm of svphilis "almost exelusi\·ely"(in mental patients) "Droof of" "cardinal S\·m1)tom" of "cardinal symptom of" "almost if not entirely oathoo-nomonic 11 "only in" "onl.\· in" isolated AR - 11 7:)':b probability" 14(1969):199-299 DISEASE T GP L + -+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Pupils / 977 978 / IV. Pupillary Pathology: Symptomatology Table 19-12. YEAR 1902 1902 1902 1902 1902 1903 1903 1903 1903 1903 1903 1903 1904 1904 1904 1904 1905 1905 1906 1906 1906 1907 1907 1907 1908 1908 1910 1911 1912 1912 1913 1914 1918 1919 1919 1921 1921 1923 1923 1924 1926 1326 1931 1932 1935 1936 1936 1937 1942 1946 1947 1948 1950 1951 1953 1958 (continued) AUTHOR Mott Nonne Raecke Schille Widal & Lemierre Babinski Clarke Collins Marburg Mott Thomas Bertolotti Dufour Dupre & Camus I I irtz & Lemaire Schwartz Grasset Maradon de Montyel Babinsld Buttino Ferrier Bumke Erb Hubner Faure & DesvatLx Jollv Weiler Bumke Goldflam Rose Dreyfuss Behr Lutz Jelliffc & White Rasquin & Dujardin Aboab Heine Bohm Lohlein Bohm Nayrac & Breton Triossi Kyrieleis Albrecht Lagrange & Lagrenge Scha~Hfle~g~rigot Tomey Bona Andreescu Meesinann Merritt & al Walsh (Duke Elder) Parsons Schulte Bonnet Okinaka & al Rucker STATEMENT ABOUT SYNDROME diagnostic diag110stic "most important physical sign" majority have AR pupils diagnostic diagnostic "exceptional" except in ''most constant physical sign" diagnostic "almost always" rn "very rare except in" ''pathog11omonic" "may be sole physical sign" diagnostic diagnostic "focal s ig11, speciric for" alwa.vs previous syphilis" ' almost constant" diagnostic "very rarely" non-syphilitic diagnostic almost. but not all have AR pupils "most important physical sign" diag110stic almost always present "most important physical sig·n" "not a single case" except in tabes or GP "never except in ' "no case Iailea to get" taoes or u¥ "in1mense n1a.1orit\'" "proves" previous syphilis non-syphilitic 'so rare it can be disregarded" "sole objective sig11 of" "almost all" syphilitic diag110stic may be "sign of" "90-95% syphilitic'' diagnostic "almost certain syphilis" "all cases suspect of CNS lues ' almost exclusively sypnilitic "exclusivel>· tabetic "almost pathognomonic" may be sole phvsical sign diagnostic all patients with AR suspect for syphilis "90'-/0 certainty" of syphilis ' may be isolated sign of" ''96% luetic" may be isolated sirn of asymptomatic neuros1ph. "almost always" syphilis "the most characteristic sign" of "almost certam sign ol" may be sole physical sign "40 x more common in lues than other disease" neurosyphilis "by far the most common cause" DISEASE T GP L + -t- + + + + + + + + + -r + + + + + -t- -t- + + + + + + + + -r + + + + + + + + + + + + + -r + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + , + + + + + + + + + + + + + + + + + + + 19. Midbrain Syndromes: Argyll Robertson Table 19-13. AUTHOR 1903 19H, 1919 1920 1920 1920 1920 1920 1920 Saeng·er Wilson Nonnc Cords v. Economo Gundlach Roll et & Bussy Santonoceto Speidel CASES 1 Grage Krambach Rossi Waardenburg 1921 1922 Wilhelm .i\losso 1923 1923 1923 Haisst Hall l\lehrtens & Barkan " " (!<l) 3.3 OU bilateral 11.S. 3 1 3 11.5. uneaual 6-7mm. n.s. n.s. n.s. semidilated n.s. bilateral bilate1·al bilateral bilateral bilateral bilateral unilateral n.s. late nhase late phase later became fixed 11.S. 6 ycai·s post cnceplfalitic late nfiase !Hehr s rie7111it10n1 11 forme fruste" 1ate nhase (Parkinson isn1) 1 n.s. bilate1·al acute 1 medium n.s. medium n.s. miotic medium unilateral n.s. bilaternl bilateral bilateral bilateral late nhase n.s. transient, durinP· reco\·er\· acute, lasted in later nhase 11 \·ears nost encenhalitic only one week dui-ing recovery (#fl) l 1 1 {lfl) (/fl!) 1 (#2) (#3) 1 1 (lf2) (#22) (113-!) " " ,." (#JG) 2 6 " 1 1 2 2 " Pette II l!J:U 1924 1924 1925 " Bielschowsky Forster Duncan Rossi Krabbe 1 2 2 (ill) (112) /i/3) 3 (ri3) II 1926 1926 1926 Thomsen Adt·ogue & Balado BernasconiCrarnei· & Adrogl,!e Cornil & al. II 1926 1926 1926 1926 1927 1929 1929 1930 1931 1931 1936 1938 1938 II Jaensch Jeandelise Meriel Warschawskii ;\.!organ & Symonds Goldbach Laignel-Lavastine & Bernal Dereux Bing & Franceschetti Jaensch Villard & al. Gaudrelet & al. Maunier-Vinard From Loewenfeld, ? sequel 1 month post infection "Ior a Iew aays";-followcd by ngidity transient, to1lowed by rigiditv 3-3 mont11s post-infection n.s. n.s. oresumDth·e diagnosis 3 years no::;t-cnceohalitis did not call these Argyll acute> H.obert::;on because of Behr's acute hut they were definition, acute dissociated pupils acute late s:tage ) dis::;oc iated, but not 1ate stage completely immobile late stuv:e to 1irtht 11 months immobile to lig-ht,prompt to near to 3 vcars slu,,..,·ish to Tirtht uro1nnt to near II II II post-enc. " " " J & II ~5 onlv a few days recovery from ophthalmoplegia acute acute acute acute acute acute late sequel from 30 nerve palsy recovery acute acute (/Ill /lf2l 3 1 (111) l\leycr TIJ\IE LATERALITY bilateral bilateral i>ilateral bilateral bilateral n.s. n.s. n.s. 2 (Ill) 1921 1921 1921 1921 IZE n.s. n.s. n.s. small uneaual n.s. n.s. n.s. l l l Staehelin PIL bilateral bilateral unilateral n.s. bilateral bilateral bilateral bilateral unilateral unilateral unilatei·al unilateral ouatei·al bilaternl bilateral bilateral bilateral bilateral bilateral bilatet"al ll.S. bilateral bilateral bilateral bilateral bilateral unilateral bilateral unilateral bilateral unilateral bilatei·al 3 1920 p small unequal large n.s. miotic miotic R>L miotic pinhead n.s. R>L R<L large large n.s. small medium miotic miotic; 11.S. n.s. miotic R3.5 L-! R3 L-! R3 L3 R3 L3 n.s. n.s. 11.S. n.s. n.s. n.s. 1 l (112) 1923 / Argyll Robertson pupils in patients with epidemic encephalitis YEAR 1923 Pupils Survey Qphthal. 1 5 1 1 1 1 14(1969).199 Numbers without parentheses denote n.s. • informdtion not given. acute sequt>l late; l persisted, post-encephalitic II ",, II numbers in parentheses II 'I seaucl n.s. - 299 number of cases; 1 became immobile (Parkinsonism) are case numbers; 979 980 / IV. Pupillary Pathology: Symptomatology cated by tabes after all? No, they were not: first, because the general symptoms (but not the Argyll Robertson pupil ) would improve or even subside once the diabetes was controlJed, only to recur when the diabetes worsened· and econd, becau e not the slightest trace of a syphiliti~ le ion could be found at autopsy. Argyll Robertson pupils were not common in diabete but_ the~ did occur. In most patients the syndrome wa typical m all respects: both pupils were small or of ~edium size. The light reflexes were shallow and slugg1 h or lo t altogether. The near-vision reactions were bri k, and not prolonged when the patients again looked far away; and the extraocular muscles were not involved. 4. Multiple Sclerosis There ha been general agreement that Argyll Roberton pupil are rare in multiple sclerosis, even though other ocular igns, including oculomotor defects, are so frequent in thi di ea e. In a few cases that came to autopsy, the pupillary sign was found to have been cau ed by a sclerotic plaque in the midbrain, without coincident yphili . There have been so few cases reported that only the results of some larger statistics are given here a examples (Table 19-14). 5. Dejerine-Sottas's Hypertrophic Neuritis, Charcot-Marie-Tooth's Disease, and Similar Conditions In these rare conditions, miosis, sluggish or fixed pupils, and Argyll Robertson pupils have been described more often than can possibly be attributable to coincidence (see Figures 35-5 and Table 35-5). The pupillary signs usually (but not always) were bilateral, fairly symmetric, and slowly progressive, so that in individual patients a gradual deterioration was followed over the course of years from normal to sluggish to dissociated and finally to immobile pupils with pinpoint miosis. Argyll Robertson pupils as well as other tabiform signs occurred more frequently in Dejerine-Sottas's than in Charcot-Marie-Tooth's disease. 5 6. Alcoholism The question of whether alcoholism could cause the Argyll Robertson syndrome has been argued back and forth a good deal. It was known generally that chronic alcoholics often had abnormal pupils: when they entered the hospital their pupils often were small and sluggish, or they failed to react to light altogether. It often was not possible to test near-vision reactions because of acute delirium or other disturbances of consciousness. In severe cases with toxic amblyopia due to alcohol, there were, indeed, other tabiform signs such as ataxia, pains, and loss of tendon reflexes. In some of these patients small, dissociated pupils were found, and vision was not poor enough to explain the absent light reflexes. Similarly, in patients with "acute hemorrhagic encephalitis 5. See, however, the section dealing with pupillary findings in these diseases in Chapter 35. Table 19-14. Argyll Robertson pupils in patients with multiple sclerosis YEAR AUTHOR 1890 1901 1902 1905 1905 1911 1918 1924 1924 1933 1947 1950 Uhthoff Probst Cestan Berger Uhthoff v. Rad Schreiber Larrranoce & l'llar□ uezv Wexberrr Abramson &Teitelbaum Walsh Savitzky & Rangell From loewenfeld, FREQUENCY Survey 0phthal. 1 1 0 2 1 2 1 0 1 3 2 5 14(1969): in in in in in in in in in in or in of AR pupils 100 cases 51 cases 35 cases 206 cases 150 cases "large group" 330 cases 52 cases 43 cases ? cases 3 "all told" 264 cases 199-299 superior" (Wernicke's encephalopathy) Argyll Robertson pupils could be observed; this was not surprising in view of the many small hemorrhages in the midbrain area which were typical in this condition. But in many less severely ill alcoholic patients it was questionable whether there was indeed a genuine Argyll Robertson syndrome: in most cases the light reflexes returned after weeks or months of abstinence from alcohol, as their general condition improved. The incidence of permanently dissociated pupils was low in alcoholics, and, if a case was found, the possibility of complication with syphilis had to be kept in mind. This was true especially in patients described before Wassermann's time. Considering the many thousands of alcoholics examined, the total number with Argyll Robertson pupils possibly due to alcohol alone is not impressive (Table 19-15,A), and many authors have vehemently denied that alcohol plays a role in the production of the syndrome (Table 19-15,B). Since chronic alcoholics are not responsible for their actions some of the time and are often neither accurate observers nor reporters, it is probably safest to go to great lengths to disprove the possibility of syphilis when Argyll Robertson pupils are found in such patients. 7. Syringomyelia Almost every large textbook will mention that Argyll Robertson pupils occur in syringomyelia, but the factual evidence for this statement is, to say the least, extremely slim. Only a few case reports have been given, and in these the connection of the pupil syndrome with the disease was not convincing. The patients were either known or later shown at autopsy to have had syphilis in addition to syringomyelia; or at least this possibility had not been ruled out with certainty (see Table 35-9). 8. Tumors and Cerebrovascular Disease Light-near dissociation of the pupils was found in patients with nonsyphilitic lesions that involved the rostral midbrain. These cases were often said to be extremely rare, but they actually have been observed in impressive numbers, as can be seen from Chapters 42 19. Midbrain Syndromes: Argyll Robertson Pupils Table 19-15. A Alcoholic patients with (non-syphilitic) Argyll ljtj7 l 90 ll95 b96 1902 1904 1905 1905 1907 190tj 1910 1910 1911 1912 1913 1900 mental natients '.lloeli 65 sc\·ere alcoholic Epcron Boedecker severe alcoholic Siemcrling 9160 mental patients acute toxic Gamble i.\leyct· Korsakoff's syndrome Nonne H60 alcoholics Spiller severe alcoholic Retz lai, ~~5 alcoholics i\onne 1066 alcoholics J\Iar1-,•1.tlics } same clinic, see 1905 Weiler 900 patients, 18 alcoholic Nonnc alcoholic Nonne severe alcoholic :\Ices alcoholic YEAR 1886 1892 1896 1897 1902 1902 1903 1903 Robertson TOTAL GROUP (or detail, if given) A THOR B. Authors 981 Alcoholism and Argyll Robertson syndrome YEAR ' transient / AR pupils YEAR 1913 1915 1915 1919 1926 1930 1938 3 3 1 15 1 1 18 1 4 18 1939 1942 II AUTHOR Pf1U11:er Mayer Nonne Fuchs Barre & Lieou Camliuer Schaeffer & Merigot de Treigny Hermann Secunda & Trowbridge 1 II 1 II 1954 3 1 Okinaka &al TOTAL GROUP (or detail, if given) AR severe alcoholic alcoholic alcoholic acute toxic alcoholic alcoholic psychosis 3* l* 1 1 1 1 alcoholic l* alcoholic 180 chronic alcoholic 24 Korsakoff's syndrome 129 delirium tremens 163 other alcohol. osvchoses 2121 medical patients 3 4 8 3 6 1 only denying that permanent AL'TIIOR Bernhardt Charcot lloche l\Iobius Dufour Nonne Collins Mott From Loewenfeld, Survey 0phthal. Argyll Robertson * YEAR - 1904 1906 1907 1911 1911 1913 1913 1914 (+\ - /+) - syndrome is fow1d in alcoholics AUTHOR Schwartz Rodicl & Caus Bumke Barnes Bumke Assman l\Iaas Firth without syphilis * YEAR (+\ 1914 1914 1923 1925 1926 1927 19.n 1951 - - (+) AUTHOR Kehrer Nonne & Wohl will Lohlein Behr Danis & Coppez Wilbrand & Behr Constantinesco Wenda * +) +) t\ t) (+) ·14(1969):199-299 - " oenial or severe doubt that permanent Argyll occurs occasionally (no case presented). Robertson syndrom occurs and 44 (see Tables 42-6 and 44-16). Pinealomas, collicular tumors, tumors projecting into the third ventricle and exerting pressure caudally, and tegmental lesions due to neoplasm, hemorrhage, or vascular occlusion abolished the light reflex. More remote space-consuming processes that affected the area indirectly via pressure or interference with its blood supply also could cause pupillary reflex rigidity. Unless the midbrain damage reached far enough ventrally to include the oculomotor nucleus, the contractions to near vision were spared. Such dissociated pupils often were found together with impairment of upward gaze (Parinaud's syndrome) and with lid retraction; and these defects together localized the lesion in the rostro-dorsal midbrain. Whether such cases should be grouped under the name of Argyll Robertson has been a subject of contention for many decades. The chief objection to the use of the eponym was that these pupils were said always to be large. This, however, is not true. In a sizeable number of patients the pupils were small (see Tables 42-6 and 44-16); and just as the optimist considers the same glass of water half full that the pessimist has described as half empty, it is a matter of opinion whether to group the medium-sized pupils with the large or with the small. in alcoholics; (+) very rare but As seen in Chapter 10, a young adult's pupils are smaller than they should be if they measure less than about 6 to 7 millimeters in the dark, and, since these patients' pupils fail to react to light, a diameter of less than 6 millimeters must be considered relatively small (Figure 19-17). Most of the cases described in the literature as "medium" in size fall into this category. When this is considered, it becomes evident that in many patients with midbrain involvement due to tumor the pupils were not actually mydriatic but only seemed to be large, when examined clinically, because they failed to respond to light. Furthermore, vascular lesions at the diencephalic-mesencephalic border zone brought on Argyll Robertson pupils with miosis (Table 44-16). The chief reason given for rejecting the use of the eponym in these cases is thus erroneous. On the other hand, the course of the disease and the details of the general symptoms differ so much from those in patients with syphilitic Argyll Robertson pupils and "spinal miosis" that there seems not much sense in belaboring the point. To avoid controversy and confusion it may be prudent to refer to such nonsyphilitic cases simply as "dissociated pupils," making the mental note that in I I I I I I 982 / IV. Pupillary Pathology: Symptomatology ome of them the pupillary reaction conform in all detail to the definition of Argyll Robertson pupils. Often, but not alway , both pupil were involved in patient with di ociated pupil due to tumor or va cular accident . Thi tendency i not difficult to under tand, ince the damage resulted in most cases from pre sure upon the small region around the rostral end of the ylvian aqueduct and ince va cular lesion often affect the reticular formation of the rostral brain tern, which impairment lead to bilateral mio is. In many ca e the course wa rapid. In patients with tumor uch a pinealoma the light reflexe became luggi h within day , and a hort time later they were abolished altogether. Soon thereafter, the near-vision reaction al o were lo t, o that the pupils became large and fixed a the intracranial and intraventricular presure ro e quickly when the aqueduct was occluded and pre ure from the tumor began to affect the midbrain tegmentum. When the pres ure was relieved surgically, the pupils could resume their reactions if the mass did not invade the midbrain. In patients with vascular le ion the onset was abrupt. When the lesion was only mall, ome improvement of pupillary function could develop later. In ome tumor ca e with a lower course and papilledema present for ome time, there was optic atrophy, and the pupils failed to respond to light because the patient was blind; but usually vision was far too well preserved to explain the absence of light reflexes by damage to the afferent pathways. In a few patients the pupil were di tarted or ectopic (Wilson, 1906), but usually they were round. Reports of patients with cerebral hemorrhages and dissociated pupils were not quite as common as reports iC t ------------- -- Y r T Y T of those with tumors, chiefly because patients with small hemorrhages tended to recover, so that no permanent pupil defect developed and no autopsy became available. After massive hemorrhages or vascular occlusions, on the other hand, the patients often died soon, and their poor general condition made testing of the nearvision reactions impossible. Further, in most cases with autopsy the lesion was too diffuse to be useful for localization of the pupil syndrome. 9. Trauma to the Eye or Orbit and Apparently Spontaneous Occurrence of Dissociated Pupils During the last century reports of trauma to the globe or the orbit, followed by a mydriatic, fixed pupil and disturbances of accommodation, were not rare. Toward the turn of the century an interesting sequel to such accidents was noted: after many weeks or months the large pupil gradually became smaller and slowly regained its capacity to constrict to near vision, while the light reflexes remained defective. Dissociation between pupillary light and near-vision reactions thus could be caused by trauma to the postganglionic efferent neuron, in the absence of syphilis. At about the same time patients were seen with similar large, dissociated pupils but with no history of trauma and indeed with no known medical problem whatever: they had been and remaine? in perfect general health. The mydriasis, often associated with impaired accommodation, had come on suddenly and spontaneously, to be followed weeks or months later by the slow return of accommodation and of pupil contractions to near vision, with no improvement of the light reflex. .. ~1-==s-=:::.:--:::.:--========::======1 Y l~-----\---~-.. _--_---;---~~----=v-=--------::.==---1 E 3 FY.I NV. E 2 I FV. NV. I FV. 0.1 sec.-+ Figure 19-17. Light-near dissociation due to pinealoma. The patient was a 13-year-old girl with a pineal tumor. She had upward-gaze paresis. When she tried to look up she developed convergence nystagmus. Accommodation was not impaired. Her pupils were equal and reacted poorly to light (A and B). W_hen short tight flashes were presented in rapid succession the pupils could barely follow a I-cycle/second rate (marked by arrows r in C); and on constant exposure to bright light the constriction measured only 1.2 millimeters (D). In contrast, the reactions to near vision were prompt and extensive (E). Note that a pupillary diameter o~ 6 mm in darkness is rather small for the patient's age, especially in view of the defective light reflexes. (From I.E. Loewenfeld, Survey Ophthal., 14 [ 1969]: 199) 19. Midbrain Syndromes: Argyll Robertson Pupils While the dissociation between the absent light reflexes and good contractions to near vision was common to these cases and to Argyll Robertson pupils, it was soon realized that the new condition differed from the Argyll Robertson phenomenon in several respects, and that the patients, in fact, had tonic pupils (Table 19-16). The Argyll Robertson syndrome usually was bilateral, but these cases were unilateral; Argyll .Robertson pupils were miotic, but these were large; accommodation was seldom involved in the Argyll Robertson syndrome but was often involved in the new group. The near-vision reactions were also different: constriction to near and redilation to far vision were prompt in Argyll Robertson pupils, but in these cases the contractions were delayed and very slow, and redilations were sluggish in the extreme. Clearly, these were not Argyll Robertson pupils at all (see Table 24-8). During the following decades the tonic pupil syndrome was defined, and its nonsyphilitic nature was confined. But even after the distinction between these two syndromes had become clear, a number of authors continued to refer to cases with tonic pupils as "true reflex rigidity," "post-traumatic reflex rigidity," "posttraumatic Argyll Robertson syndrome," "Argyll Robertson syndrome with mydriasis," or, less emphatically, as "seeming reflex rigidity" or "pseudo-Argyll Robertson syndrome" (Table 19-16). These cases, mistaken for Argyll Robertson pupils, played a role in the discussions about the site of the responsible lesion, as will be seen below. In all of the reports, however, the description of the near-vision contractions, the sequence of events, and other details leave no doubt that the patients had tonic pupils. 10. Herpes Zoster Patients have been described in whom the Argyll Robertson syndrome was said to have developed after an episode of ophthalmic herpes zoster. However, when these reports are studied with today's hindsight, it appears certain that they also were not Argyll Robertson but tonic, dissociated pupils. The more explicit were the descriptions of the clinical history and the type of pupillary movements, the more likely this conclusion became (Table 32-6 and Figure 32-16). Cases with Argyll Robertson pupils after herpetic encephalitis are, in contrast to the frequent peripheral lesions, rare. 11. Head Trauma and Other Impairment of the Third Nerve A last group of patients with dissociated pupils had recovered from severe head injuries, ruptured aneurysms of basal vessels, or similar damage involving the third nerve in its intracranial course. In most cases there was paralysis of all muscles innervated by the third nerve at the time of injury, and the pupil was large and fixed. After months or years the pupil was noticed to have become smaller, and the extraocular movements were partly restored. Such patients often showed extensive / 983 pupillary contractions when they looked near, while the light reflexes remained absent. As in the cases just described with orbital or ocular trauma or with herpes zoster, these reports played a considerable role in the debates about the location of the lesion responsible for Argyll Robertson pupils. But again the condition differed from the Argyll Robertson syndrome in some important details. The Argyll Robertson syndrome was limited to the pupil, but in this group of patients the extraocular movements also were abnormal. Typically, the eye could be moved horizontally and the patient could converge, but the globe remained fixed when the patient tried to look up or down, so that vertical diplopia resulted. In addition, the paretic lid, which drooped in primary gaze, snapped up whenever the patient tried to look up or down and when the eye was adducted. The pupil constricted not only on near vision with convergence (as in the Argyll Robertson syndrome) but also when the eye was adducted during associated lateral movements and on attempted upward or downward gaze-in other words, whenever the patient tried to innervate any muscle served by a branch of the third nerve. This posttraumatic, dissociated pupillary phenomenon was later found to be part of "oculomotor misdirection," or "dyskinesia," and its mechanism was explained (see especially Chapters 11 and 23). 12. Other Causes Argyll Robertson pupils were observed in connection with a number of pathologic conditions such as senile dementia or cerebral arteriosclerosis, but there was no consistency in these scattered reports, and in some patients the pupillary finding was almost certainly coincidence. Table 19-17 contains the surprisingly small number of actual cases mentioned in the literature reviewed. Before Wassermann's time these reports were viewed with suspicion as possibly complicated by neurosyphilis. 13. Incidence and Characteristics of Argyll Robertson Pupils in Our Unselected Patient Group In our unselected patient group the incidence of Argyll Robertson pupils agreed more or Jess with the literature (Table 19-18 and Figure 19-18). Of the sixtyeight patients forty-four were men and twenty-four women. By far the largest group of patients had syphilitic diseases of the central nervous system (43 of 68): and among these diseases, the percentage with Argyll Robertson pupils was quite high (24.3%), though not as high as in the statistics around the turn of the century. Among the nonsyphilitic diseases there were rare cases with diabetes mellitus, with tumors affecting the rostral midbrain, with nonspecific central nervous system infections, and with head trauma. In two patients with multiple sclerosis the possibility of syphilis was ruled out with confidence, and it can be assumed that demyelinated plaques were responsible; but we have no anatomic verification for this belief.·Tn elderly patients with 984 / IV. Pupillary Pathology: Symptomatology Table 19-16. Tonic pupils mistaken for Argyll Robertson syndrome YEAR A 1896 1895 Schwartz 1896 1897 1898 1900 1904 1904 1905 1906 THOR HOW CALLED incomplete CAUSE AR unknown To:-;rc ? U FEATURES near contractions OF REACTIO~S normal for vears Seggel 1#fil;------t--:r:;;ej-fli-:e~x;-:r:rig~idiii:i'ty~-•---+..::o~r~b~i~ta!:lc...:::tr~a~u~1~11~a=-+-;~~l+...;U~·+..:"coe:!:a~r...,!.r~e::.sl:!po~ns::.e~>:,.n~o~r~m~a~l_.....,..,-----" #2 reflex rigidity unknown 1\1 U eserine contrat'lion > normal aspar unilateral AR unknown L U super-normal contractions to near Wilder unilateral Att unknown L U super-normal contractions to near Leszinsky unilateral AR unknown L U preceded by internal ophthalmopJegia Levinsohn reflex rigidity unknown L U near responses very slow Aeenstoots no term used unknown L U n. s. Magnani traumatic mydriasis eye trauma L U distorted; movement not described Cosmettatos no term usea J1it in eye L u n. s. Axenfeld ill reflex rigidity eye contusion L U n.s. (became medium size later) '#;;;3;-----+-'-r':-e"flc:e:.:x~r;iig,;ic:d;.;.i~ty!.,-----+:::ey.:::::.e...:t:::r:'..!a~u:::m~a~---l~L;___i~U~~".:.m:!).:.'O.i:t:!.'o::.'n~ic!.!'!-!'..::t'-oc!.n~e::.'a!.!r=; :!-bc:e'.!c=.a:::m~e=s:::n~1al,l"l_e_r...,l-a.,..t ---1 1906 1906 Brautigam AR eye trauma t:i u ovaJ; slow & 1ong-1asling near contraction Caspar ~!l-=.4 _____ -iru~n~il:'ia;::t:':e::-r:::a.:.._l ______ +i'.h70 it~o=:r~b~it~al~r~im~-+~S~-;:U;..+~s.:::u~p~e=-r~-'.:no~r'.:m~al~n~e~a~r:_..:;c:_::o::n~t=.r;_:a~ct~i~o " #5 reflex hit orbital rim S U super-normal near contraction 0e:i;,.dit::-c-v------+:.:u.::n~Kn.::.o:::.w.::n::::...::..:.~-+..;:L:_i-~ " "#:-;,7c--------,f---=--=r:,:i u+--:::.s;10!:'..1:::v.::.,-,e:.:a:::.r::..:.:c:.:o::n:,.t1:.:·a:::c::t;..,i..::o:.::n::.; :.:a:;..::os::e::n;t;;.,,, kn"""'e"""'e-J~eccr=-k----1 1907 1911 1911 1912 1912 Ohm unilat. reflex rigidity orbital trauma L U supernormal, tonic near contraction Magitot AR unKnown 1\1 Ll tonic near contraction to oinooint size ogt Attw1tnmyarias1s eve trauma L u n.s. Galezowsky AR ui1Known L U "tonic" contraction to near Goldflam In peculiar detect unknown l\I U oistortea; near response tonic " '#;:;2~----+---'n'-'o"'n:.:_c.,l,'-u::::e';-t.,.:ic"-";Ac"R~------+...:u.:::,.:;,k.:::1.::10::.:,:.:..v'...'.n ____ -l--l\;:l~-:-U~~v::.:e:::1:.:·y:::..::.s::;:lo:c,:..avc:t:.:..o~n=-e.:.ac::r:.:a:.t,:.:,d:;.:::s:.;:lo'-' t--;-1;:9 _______ 71;:3-t--;'B':'ecch~r:1913 l\lorax +-'a'?tP~Pa::.ro:·e:::n:.:..t::....!.r.:::e~fl'-'e"-x'--"r-"ie:c.ic::'d :..:ic::.tvL..-1--'u,,_n:.:..k'-'!.·nownL AR ?,-----+-7+-:?~.- 1913 1914 1914 1916 1917 Veller LerPerger Thompson Bachstetz Paginez & Vallerv-Radot traumatic AR AR AR - type unilat. reflex rigidity eye trauma unknown unknown orbital mass L L L ~I no term hit in eye L 1917 1918 1918 Roemheld Bollack reflex rigidity traumatic AR snot in orbit hit in eye :II L used u oy 1ixea, iarge 1Juoil; slow to near 7to:::,:.:1 + 4preceaea ,~,mc::1=vo i=-c:;:"~to=n"e"a'-r=='-"'==-==---"'-"=c=.....----i U U U U preceded by fixed pupil; later tonic near reaction near reaction very slow n. s. slow to nea1· and slower U U medium size to far near responses very slow first int. ophthalmoplegia; later medium size Krueger~#~l:;--------t-A_R=:';--:,:------,,---:,-;:,-------+~u:.:.n ___ -1f.--;;L=--!-;U:,..+-"n:.:.~s~.~.---,.--,--,,--,.-,------;-,--,,.,,....,,..,,.-===-=---~ 7k=no~w:.:r::..1 " #2 unilateral AR unknown L U very slow to near &rar; .,.~~ to pilocarpine " -';#;';3;-----+---';A;.,R~- ===="'-----------jf-c::!u'...'.n;k.:::n~oc::w:.:n~----l-~L!....j.___;:U~__c_su~p~eLr...c'..'.-n~o_:cr'-ru~al~to~-n~e~a:.:..r:.:, -'-v:-e-1-,·y,....:::s,-lof,c.:vc;t'=o'-'f"a"'r=.::_ 1918 1919 1919 1920 1920 1920 1921 1921 1921 1922 1922 1923 1923 l\lagitot traumatic AR broken maxiua L u preceaea oy opntmumopiegia Jelliffe & While AR orbital trauma n. s. n.s. A. Lowenstein traumatic AR trauma S U "myotonic' to near Dickinson typical AR unknown L U n.s. Fleischer & Nienhold traumatic AR orbital trauma :\! L' preceded by ophthalmoplcgia Mae:itot & Bollack traumatic AR surgical (orbit) L U preceded by iridoplegia; later became small Gehreke tonic unknown S U describes tonicity Jw1ius pseudo reflex rigidity trauma L U "myotonic" near response Roemheld traumat. oseudo-tabes head trauma L U "myotonic" near response Bielschowskv traumatic reflex rigidity hit orbital rim L U "myotonic" contraction to near Keller true reflex rigidity diphtheria L U slow to near, tonic to far Dreyfus typical AR orbital trauma L U preceded by int. ophthalmoplegia; became small Duverger~#~lc-------lf---t!cr:..!a'...'.u!.!n'...'.1:!'!a:!'.t'...'.ic::..·:;:., AR~-----+...:e;c,\r_:'e::....::c:.:o'...'.n'...'.t:::u2.s'...'.io:'..!n::...._-1--ll~l::.+-:-U~-+...1Pi..:r:..!·e::.-c:..!e~d~e~d~b.L..'vic:r.:.i::;d~op " #2 traumatic AR eye contusion L U preceded by iridoplegia; "myotonic" to near 1923 Weber AR with mvdriasis unknown L U "tonic" to near 1925 Behr traumatic pseudo-AR eye trauma L U tonic to near 1925 Inman & Lawson non-luetic AR unknown L U 2 cases tvoically tonic 1923 llloore non-luetic AR unknown L U 2 cases, "tonic" to near 1926 Genet traumatic AR eye trauma L U preceded by iridoplegia 1--.c.1.c.9-e-2-e-6-+-'-N • .,:i.c.ec,ls ... ·e:..1=-1 _&_S:..t:..;e,..,g'=m=a_n~-+--''~'o:,,n.;..-...:1..:.uc:e..:.t:..ic:...· _in_a_c_t_i_o_n ___ +-u_n.,.k__,n.,..o_,11,...·1_1 ------,f---cL,--t-=Bc-t_2_b_o_u_t_s_in_e_a_c_h_eye. preceded by iridonle<ria 1926 Weill Reys&Dreyfus AR orbital tumor L U n.s. _________ -+--=e=ye_t"'r-=a~u=m=a'--,--t~Lc...+~U'-+_p=re~c~e~d":-e~ia":-c'by internai ophthalmop.-"le=-i=rr·ia.:...... ____ -1 1_=-l"-92=-7-'---l--'-'Re"')..,_I'.::S_.:..42=----------t--..cA::.cR:..:..:? 1927 Vetter & Tournav AR unknown n. s. preceded by internal ophthalmoplegia 7i='a------j t-c-1-=-92=9-+--=nu-=m-u_;_ v·~--=Du,.....,t_e_n-'-,p-s~lf....,1,---+-~A,..R~----------+-~o=rbital mmo r s+..::;.;..Ju,...J:p'..:r..::e:.':c:.':c~oe~ab~)'. ...;i::.:n;te::::r~,::.:1al~:::.opt:.;.:ht,:;h::al::;.::m.::o?p"ilc:e 1931 Adie pseudo-AR unknown 1 , tome reactions ano mslurbed DTRs 1931 l\loore non-luetic AR unknown L U 8 patients with tonic syndrome t-s-19n3"'a"'-t-B"'ie='i1r,i-:::n-=-g---------t-::r:-::e:-rrue::-:x:--::r"1g=1u:r.1"ty::------+,.,u-=n=1<n"'o"'w"'n,------l--'.-L+-TT"u+-n=-e;,a"'1"'· -=r"'e""a""c=t10"'n,...,.,v"'e"'r""y~sl"o""w,--------------1 1936 Jaeger reflex rigidity unknown L U 7 cases, undoubtedly tonic 1936 Laignel-Lavastine traumatic AR trauma(orbital) L U preceded by ophthalmoplerria 1937 !\!eyer seeming reflex rigidity unknown L U 5 cases imoaired DTRs and tonic ouoils 1939 Newman & Jacobson pseudo-AR unknown L B tonic pupil described; DTRs disturbed 1954 Pours ines & Alliez AR unknown L U preceded by iridoplegia 1962 Unger & Umbach post-traumatic AR orbital trauma L U preceded by ophthalmoplegia From Loewenfeld, Survey 0phthal. 14(1969):199-299 L = large; M = medium; S ~ small; U = unilateral; n.s. = not reported; ? = incomplete note (of reviewer); AR = Argyll Robertson· syndrome; * = German term "refl ectori sche Pupil 1enstarreM. indi eating absence of 11ght reflex, with near-vision reaction present (often loosely usE:d as equivalent of Argyll Robertson syndrome). 19. Midbrain Syndromes:Argyll Robertson Pupils / 985 Table 19-17. Reports of Argyll Robertson pupils in various diseases YEAR AUTHOR 1880 lb96 Erb Siemer ling lb96 1897 ]900 1901 1902 1904 1903 1906 1907 1912 1912 1913 1913 1921 1923 1924 192i) 1923 192:3 1923 l\loeli l\Ioeli Dejerine l\1aradon de l\1ontyel Schulze Schlesinger Uhthoff Bertozzi Retzlaff Rose Winaver Behr Feilchenfeld Jelliffe Lechler Fuchs De Ca.1J.ite Dupuy Dutemps Froidbise Lenz 1926 1926 J 927 1930 1933 1934 1934 1934 1935 1935 1935 1935 1938 1939 1947 1949 1953 1954 1954 Danis & Coppez DISEASE II 11 II Barrett Kielsen & Verity Dosuzkov Aliquo Mazzei Costa Lenon Werner Jacquet Nagy Roger & al. Favorolo Gare in Costa Lenon Walsh Sommer II II Kissel & al. Okinaka & al. From Loewenfeld, Survey Ophthal. (nc) • no case report, 1 case advanced dementia, 2 cases nicotine poisonif!g_ among 9160 mental patients: 19 senile dementia, 4 epilepsy, 15 "hysteria" 7 paranoia 3 cases bubonic plague 1 case herpes encephalitis; sometimes carbon sulphide poisoning 1 case poliomyelitis zl cases O_l_ll age 1 case "croupous pneumonia" 1 case amyotropnic iaterai sc1eros1s sometimes in epidemic cerebra spinal meningitis 1 case dementia praecox sometimes in senile dementia· 2 cases meningitis occasionally in cerebra-spinal meningitis Friedreich's disease, polyneui-itis, periodic psychosis (nc) rarely congenital or brain disease in childhood (nc) 1 case assumed congenital anomaly 2 cases hy_2othyroidism (syphilis not excluded) 1 case cerebrospinal meningitis rarely lead or alcohol poisoning (nc) rarely infantile paralysis infantile hemiplegia (nc) acute glaucoma pontine lesions; 2 cnses epidemic meningitis defects of cerebral circulation due to diabetes, nephritis, JJernicious anemia, leukemia, aortic disease. arteriosclerosis seldom in polyencephalitis, sulfur- or CO poi oning, senile dementia (nc) 2 cases Friedreich 's disease 1 case....Qol_yneuritis an unsolved case of CNS disease tegmental disease meningitis Jnc} typhus 1 case diphtheria (large pupil) 1 case tetanus 1 case "familial Parkinson ism" 1 case measles encephalitis old age (nc) rarely in non-specific brain disease (nc) 2 among 106 cases with typhus sometimes without known cause 34 cases without known cause It II II II 1 case "combined spinal sclerosis and hyperchrom ic anemia among 2121 medical patients: 1 Tbc meningitis; 1 cerebral arteriosclerosis 14(1969):199-299 only general statement. advanced arteriosclerosis, tiny midbrain foci may have been the cause. One patient had Charcot-Marie-Tooth's disease (see Figure 35-5). Another had been treated with pilocarpine for glaucoma over an eleven-year period, and the development of Argyll Robertson pupils had been masked by the miotic effect of the drug. When the eyedrops were stopped for 5 days, preparatory to the pupilla.ry test, the pupils refused to enlarge to normal size, and a striking light-near dissociation was discovered. The patient was then tested for syphilis, and strongly positive blood and cerebrospinal fluid reactions were found. It is, of course, possible that in some cases the pupillary syndrome was not related to the patient's presenting illness but was merely coincident. The age distribution among the 68 patients with Argyll Robertson pupils is shown in Figure 19-19. Compared to the unselected group of eighteen hundred cases, the percentage of middle-aged patients was high, with none younger than 20 or older than 66 years. Many of our patients had tiny pupils, and in most of the remaining ones the pupils were smaller than normal in darkness, with a mean dark-adapted diameter of only 4 millimeters (Figure 19-20). In nine patients, thirteen pupils were 6 millimeters or larger in the dark (Table 19-19). The incidence of syphilitic diseases was not lower in these patients than in those with miosis. But in eight cases the residual reactions to near vision also were very poor, so that the pupillary syndrome approached that of internal ophthalmoplegia; and in one case there was, in addition, a flaccid ptosis on the side of the pupil defect. One patient with multiple sclerosis had large pupils with fixed light reflexes and brisk, fairly extensive contractions to near vision (Figure 19-21). Vision was normal. I 986 IV. Pupillary Pathology: Symptomatology Table 19-18. The frequency of Argyll Robertson syndrome among 1800 unselected cases DISEASE E TITY ELECTED NUMBER OF CASES CASES (TOTAL) 1800 CNS Sl_Ehilis non-specil'ic CNS infections multiple sclerosis traumatic brain lesion post-concussion syndrome space taking processes degenerative CNS conaitions cerebral arteriosclerosis cerebro-vascular accidents paralysis agitans essential h_yeertension diabetes mellitus hyperthyroidism autonomic nervous attacks _schizo_phrenia _ -~non-specific manic deeressive :es_ychoses es_ychoneuroses endogenous nervousness glaucoma experimental subjects % ARGYLL ROBERTSON UMBER OF CASES WITH ARGYLL ROBERTSON UNILAT. BILAT. TOTAL IN DISEASE ENTITY 28 * 40 68 3.8 177 137 115 55 51 34 82 93 29 34 119 28 55 81 14 5 2 2 29 3 0 1 0 2 43 8 2 3 0 3 24.3 5.8 1. 7 5.5 0 8.8 2.4 2.2 0 0 0 10.7 0 1. 2 53 0 1 0 1 0 0 0 1 0 1 ;.::: ;.::: 1 0 0 0 2 0 0 2 0 0 0 0 204 43 74 0 0 1 0 0 0 0 0 0 0 0 1.4 195 0 0 0 0 0 0 0 3 0 1 *: Cases marked "unilateral" had the Argyll Robertson dissociation in one eye only; but only 7 of these were truly unilateral. In the remaining 21 the other pupil was either miotic or larger, with impaired reactions to light and to near vision. 40 w 35 a: Cl z ~ z 30 :E 0 0 (f) z iii 0 a: ....J ....J >CJ a: <( -:12. 0 24.3 25 20 15 10 5 0 0 ~ 0 0 ~ ...J ~ 0 I- .!!? i: C. >, u"' ~-Q Q) c,U - <ll-2! C: C: en oen zen z z u u en ::i: u C: -.;: 0 C: Q) .Q E er~"'~ :, ...J ~ C: 1-'ii:j m "'0 :, 'O uC: C: >, oen <.) I iii 0 a.. "'"' Q) :, ci>~ .oco a, o:::i: E -~ 'O ·o >, £: Q) C. >, I 1.2 11111I 0 u"' --.>< C: :: ..c 0. Eu 0 co £<C :, <C Q) 0 N E 0 0 I co ·2 u en I I Q) "' -~ ·u; "'0 <ll.C Q) ~ u>, C."' 'O a, Q. I u ·2 co ::i: 0 0 0 1----1-1--+-1--t----- "' "' e :, Q) a, C: 0 .c u>, "' <l)·<I) 0:, "' Q) C: C: Q) "' 0):, co 'O > C: w Q) ~ z Cl) -<I) E co-u C: Q) co ·- 0 u:, a a>-- E.o :, a;en C. )( w Q. Figure 19-18. Incidence of Argyll Robertson pupils in our unselected group of L,800 patients. The columns correspond to the numbers in Table 19-18. The horizontal line shows incidence of Argyll Robertson pupils in the entire group (shaded column to the left). 19. Midbrain Syndrome : Argyll Robert on Pupil Table 19-19. Light-near dissociated pupils of 6 mm diameter or larger DISEASE PATIENT T.C. M.G. S.K., B.N., T.S., F.T., 1 c.w., G.W., E.W., 1 987 ~!~ DIAMETER lmm\ RIGHT LEFT enceehalitis CNS SYI~hilis multiple sclerosis CNS syphilis CNS s_yphilis tabes dorsalis CNS syphilis congenital syphilis CNS syphilis c:r21 0"55 49 ~ 47 44 ~ 26 ~ 50 6.4 6.0 6.8 5.5 6.5 7.3 6.8 6.2 6.1 AR*l 6.7 6.2 7.2 6.4 7.0 6.0 7.2 5.0 5.9 OU OD OU OS OU OD OU OD OU PUPIL MOVEME TS all ver.}'. poor OU QOor OU fixed to light 1 fair to near OU *2 all very poor OU all veri eoor OU fairl,}'. good, dissociated OU-*3 almost fixed OU veri eoor OU fixed to light, reduced to near OU * 1 : None of these pupils showed tonicity, and all were of the Argyll Robertson type of dis so ciation. *2 : This patient had superior rectus paresis on the left side. *3 : This patient had ptosis on the right side. Is 1 14 t 6f A ~: ~ r:=: : :: :: : : :: 13 12 t II /' ,, '~ ----1: -<( 8 7 :i: u 6 7. :5 z 5 : : : : :: :: : : : ' : :: : ~ ~ ::i IN 1800 CASES I ~~0-..... :::;2l >! t~ .. ~,1 _, ~0 ' 0 \ AGE IN YEARS ➔ 68 PATIENTS 4 i g3+ AGE DISTRIBUTION : :: -:: ::: : : : ::: ::: : ":"' : : : : :: : : ~ ~= : : :~ :: :: : '\ : : : : : : : ::: '' : : :: : : : : ~'',,,,,_ : : : : .;;, □,-1-,~r=~;.;...i' ' ~I I ro oo 90 100 ' ~ ~ ~ ":' 0 B i'.isf 0,,,,,,,,, ~~~ 7 •0~<:=:~--------~-----10 20 30 ~ ~ 50 tlJ 70 80 90 100 AGE IN YEARS ➔ Figure 19-19. Age di tribution among 6 patient with Argyll Robertson syndrome. A: Each column how the percentage of patient in each ucce ive 5-year age group._The thin _broken line indicates the percentage for each age group m the entire un elected 1,800 cases. 8: The circles and olid line how relative frequency of Argyll Robert on patient , a compared to the total group (broken line at l), in ucce ive decade . Value ab . e l indicate greater frequency of a given age group among patient with Argyll Robertson pupils than among the total 1, 00 group, and values below l how le er frequency. ... ( 106 EYES) WITH ARGYLL ROBERTSON SYND ROME MEAN DIAMETER . . l l 4 PUPIL DIAMETER (in mm) _. . J unilateral ca e only the affected eye wa u ed and in biFigure 19-20. Pupil diameters in patients with Argyll Robe~t on syn~;~:~~;; 11 darkness for each eye. ee Table 19-19 for detail about lateral cases both eyes. All measurements were the largest diameters patients with pupils 6 millimeters or larger. 988 / IV. Pupillary Pathology: Symptomatology E. Site of the Lesion and Mechanism of the Syndrome A mentioned in the hi torical ection above, no agreement wa reached during the century after Argyll Robert on' publication a to the mechanism of his yndrome or the location of the le ion respon ible for it. The e di cus ions are traced in detail elsewhere (Loewenfeld 1969), and only a summary is provided here of the main theorie and conclu ion . For the ramifications of the e protracted quarrel , and most of the arguments, counter argument , and supporting data, the reader is referred to the earlier review. 1. Damage in the Cervical Cord The olde t theory, and Argyll Robertson's own, placed the le ion in the pinal cord. This view was only natural, a the syndrome was found in patients with " pinal di ea e" (tabes dorsalis). It also fitted well with the di coverie about the sympathetic nervous system made by Budge and Waller in 1851-1855 and shortly thereafter publicized and claimed for his own by the great Claude Bernard (1852-1863; see Chapter 6). The sympathetic fiber running up the neck to innervate the eye originated in the cervical pinal cord, and destruction of these "cilia pinal nerves" by cord lesions caused mio i . But how could the absent light reflexes be explained? Argyll Robertson proposed that the normal light reflex was not an active function of a sphincter muscle but "an isolated example of normal, temporary reflex paralysis": in darkness the normal pupil would be large, thanks to sympathetic impulses from the spinal cord; and light would paralyze the sympathetic nerve, causing the pupil to contract. When the light was turned off again, the sympathetic would recover and again dilate the pupil. A lesion in the spinal cord would abolish this sympathetic innervation permanently, and the pupil would therefore become small and fixed.6 This theory was quickly disproven. When the sympathetic nerve was cut in animals the light reflex was not impaired; and in patients with sympathetic paralysis the pupils contracted briskly to light and redilated promptly in darkness. The "cord" theory thus seemed to have been laid to rest, but toward the end of the century it was revived, and the ensuing controversy was one of the most shameful episodes in the literature about the pupil. This unnecessary fight was undertaken by a small clique of authors, mostly from the University of Wurzburg, and it was continued for over 20 years. s-FF1-A·LJ,----17F1 ----- l.r. 1111 7t--""":"'-...;1 -- I 1 ~-i=-=1 -- 7 -1-1 65 • 65I 1.l. 4 '111111 II 1111 111 $~ 11 1111111111 i::::::=7 ___ I -B I J·--- - t -----------::. ~--L-----5 l.r. l.r. 111111 -- I ~----- I --,--4 l.l. 11111 NV. .,-----------------------,--------. _5 I.I. I -1----i I FV. 0. l sec.--+ Figure 19-21. Nonsyphilitic dissociated pupils. The patient was a 21-year-old man. He had never had a venereal infection. About a year before examination he fainted without apparent reason and was sent to a hospital where all tests, including serologic tests for syphilis, blood count, and eye examinations, were negative. Eight months later the patient suddently saw double, with one image higher than the other, and he had pain on moving his eyes. This continued without much change up to the time of examination. He was found to have limitation of upward gaze due to left superior rectus paresis, with slight rotatory nystagmus. Vision was nor- ma!. All tendon reflexes were active. There was left ankle cionus, and the right radial reflex was more active than the left one. Muscle tone was increased in the lower extremities, more on the left than on the right. There was intention tremor in the upper extremities, especially on the left. The right upper abdominal reflex was weak and quickly exhausted. Skull X-rays were normal. The ccrebrospinal fluid showed increased cells and protein but tests for syphillis were negative, as they were in the blood. The pupils were large and completely fixed to the strongest light stimuli (A and 8), but they contracted to near vision and redilated promptly when the patient shifted his gaze from near to far (C). 19. Midbrain Syndromes: Argyll Robertson Pupils / 989 The motor nucleus for the pupillary light reflex was said to be situated not in the midbrain-as had been accepted generally for more than 50 years-but in the cervical cord. This center was supposed to receive stimulation from the optic tracts via yet unidentified descending brainstem pathways and to send efferent impulses to the iris by way of the median longitudinal fasciculus and (bypassing the oculomotor nucleus) the third nerve and the ciliary ganglion. A cord lesion would therefore interrupt the light reflex arc and at the same time destroy the sympathetic "ciliospinal nerves," causing miosis. To support these notions a great many hairsplitting arguments, misrepresented clinical material, and unphysiologic animal experiments were offered. And when it became obvious that the entire edifice of "proof' had begun to fall apart, the postulated lesions slowly slithered cephalad, under the smoke screen of incessant discussions: beginning in the cord (1898-1899), the lesion moved to the caudal medulla (1900-1902), thence to its rostral end (1903-1904), and finally it ended up in the midbrain after all, in the brachia of the superior colliculi (1906). It is pointless to elaborate here on the tedious ramifications of these complex hypotheses, which, as Ferrier expressed it in 1906, "remind one of the cycles and epicycles of Ptolemaic astronomy," and which were thoroughly discredited in the end. Readers hardy enough to wish to delve into this chapter of pupiliary controversy are referred to my 1969 review. 2. Damage in the Afferent Path of the Light Reflex Many authors agreed that the lesion responsible for the Argyll Robertson syndrome could not be situated in the afferent path of the light reflex in the optic nerve or tract because vision was perfect in many cases. Others objected that visual and pupillary afferent impulses need not originate in the same retinal receptors and could be conducted by separate systems of ganglion cells and fibers to the brain. This would explain the loss of light reflexes despite good vision. As shown in Chapter 3, however, there is solid evidence for the assumption that both pupillary and visual afferent impulses are generated by the same receptors, that is, the retinal rods and cones. Until recently the situation was less clear regarding the retinal ganglion cells and afferent fibers: it was uncertain whether pupillary fibers branched off as collaterals from the visual fibers in the optic tract or whether they arose from separate ganglion cells. It now appears certain that the chief supply of pupilloconstrictor im- . 6. Off a_ndon, similar theories have been proposed, suggestmg that failure of the ArgyllRobertson pupil's light reflex was due to absence of sympathetic dilator impulses (Kreuzfuchs, 1903, 1906; Buenafama Uriarte, 1935; O'Day, 1936; Leathart, 1941; Kornblueth, 1952). None of these rather odd and complex constructions has been verified experimentally. pulses reaches the midbrain by fibers from the phylogenetically old "W" (gamma) class of retinal ganglion cells, with lesser input from "Y" (alpha) and probably also from "X" (beta) cells. While-to a degree-pupillary and visual impressions thus run in separate afferent fiber systems, it remains difficult to believe that all pupiJiary fibers of the closely packed optic nerve and tract could be picked out for destruction by a generalized disease such as neurosyphilis, leaving all visual fibers untouched. To explain such isolated pupillomotor afferent loss, some authors proposed that the pupillary fibers were not intermingled with the visual fibers in the optic nerve and tract but travelled as a separate fascicle from the eye to the midbrain. They could then be destroyed without harm to the visual fibers. But there are serious flaws in this theory. These have been mentioned above in Chapter 17 and will not be repeated here. Three additional facts make it possible to dismiss with confidence the theory of an afferent lesion as the cause of the Argyll Robertson syndrome. First, in pathologic studies on the brains of patients who had had typical Argyll Robertson pupils in life, the optic nerves and tracts were found entirely unimpaired (Bach, 1889 [1 case]; Pineles, 1896 [20 cases]; Bach, 1903 [1 case]; Thomas, 1912 [2 cases]; Stargardt, 1913 [4 cases]; Rizzio, 1938 [8 cases]). Second, a lesion in the afferent path of the light reflex could not explain the unilateral Argyll Robertson syndrome, because in primates impulses from each optic tract are distributed evenly to the right and the left pupilloconstrictor nuclei (see Chapters 3, 17, and 18). Third, lesions in the optic nerve or tract reduce the light reflex, but the responses have nothing in common with those seen in Argyll Robertson pupils: there is no miosis, no anisocoria, no sluggishness of the movements. The latent period for contraction is longer and the movement faster and shorter-lasting than in Argyll Robertson pupils, with an entirely different timeamplitude pattern (see cases in Chapter 17). 3. Damage in the Efferent Path of the Light Reflex (a) The Oculomotor Nucleus When the rostral, small-celled portion of the oculomotor nucleus had been identified as the center for pupilloconstriction it was natural to suppose that damage to this nucleus would abolish the light reflex in Argyll Robertson pupils. But how could the well-preserved reactions to near vision be explained? Three mechanisms were proposed (Table 19-20). (1) The near-vision impulses were believed to be stronger than those elicited by light. According to this view, the cells of the oculomotor nucleus were damaged but not destroyed in the Argyll Robertson syndrome. They therefore failed to respond to light but could still be activated by the more powerful and long-lasting near-vision stimuli. The light-near dissociation was thus merely a 990 IV. Pupillary Pathology: Symptomatology Table 19-20. YEAR A The assumption of separate efferent fiber systems for light reflex and for near-vision reaction THOR MECIIA ISl\1 OF DISSOCIATION _, C Q) -~ bO ~ "cii ~ "O g 1 78 1 83 1 85 1 88 1 90 1 92 1 93 1 94 1 95 1 96 1 96 1 97 1 98 1 98 1 98 1898 1899 1899 1900 1900 1901 1901 1901 1902 1903 1903 1905 1906 1906 1906 1906 1906 1907 1908 1908 1908 1908 Hutchinson Gowers Blanc Heddaeus Dufour Borthen Heddaeus Kri.ie:er Schanz Baas l\lonro Thomsen lleddaeus Lcszinsh.·-y SchmidtIUmpler de Schweinitz Reber Deicrine Lcvinsohn Baas Levinsohn & Arndt Rue:e Boudinski Raecke Heddaeus Abelsdorff Axenfeld Brautigam Caspar Ferrier Ohm Abclsdorff Lacaucur Levinsohn Weste ..c: C 0 bl>-- :.:::-~ > ] Ul ·- ......> ... cJ H .3 r,... C ~ ·~ YEAR C C Q) ._... <ti C :...i <l) ~ ~ ciloi ... > .bl) <l) (.J Q) <l) r,... <ti u ~ § <ti Ul ... ..c: OJ ...... ~~ <ti ...... <ti a. c:,! Q) a. -§ o<l o.-§, Q) ·Ul Ul ..- + + + + + + + + + + +*1 + + + + + +*2 + + +*l + + + + + + + + + + + + "O 0 C Ul + + + + MECHANISM OF DISSOCIATION ...... ._... * Ql M H AUTHOR + + 1912 1914 1917 1917 1917 1917 1918 1920 1920 1921 1922 1923 1923 1923 1936 1942 1942 1942 1943 1945 1945 1947 1949 1950 1953 1953 1954 1956 1957 1957 1957 1959 1959 1961 1961 1964 1964 Winaver Deierine BirchHirschfeld Dufour Levinsohn Bauer Levinsohn Llibbert Kafka Guillain & al. Bielschowsky Levinsohn Bielschowsky Aliauo-Mazzci Edelston Nathan & Turner Bonnet Ecker & Anthony Walsh Duke-Elder Bonnet Thiebaut & Helle Kaquin Cogan Bonnet Thiebaut & Matavuli Gare in & al. Guillaumat & al Taraschi & Tosarelli Duke-Elder (Parsons) ~ § bO.,... .,... Ul ......·H > 0 H ..... <ti ·OJ ~ C: UH ::l 0 H C .9 0 ._... Ul Ul .,... :::: > <l) (.J ... <ti ~ ~ c Q) H Q) ~ Q) * Q) M ...... ~o<l <ti Ul H ..C: oo::: Ul s::._... c:,! ..., c:,!...., a. c:,! ..go<l a...C <1l bO Q) a. Ul + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + From Loewenfeld, Survey Ophthdl. 14(1969):199-299 *l • three sepdrdte subnuclei dssumed; *2 • three sepdrate kinds of cells dSsumed; *3 • duthors who did not mention the oculomotor nucleus (some dssumed d division of the pdths more peripherdlly, but these dssumptions imply the existence of separate nuclear elements). step toward complete paralysis, or a first stage of recovery from previous iridoplegia. 7 (2) The pupillary sphincter nucleus was thought to contain two different kinds of cells, some serving the pupillary light reflex and others the pupillary contraction to near vision. The light reflex cells were said to be more fragile or selec7. This mechanism of imperfect reflex transmission has been assumed also by authors who placed the Argyll Robertson lesion into the pretectal-oculomotor synapse, or in the ciliary ganglion, the ciliary nerves, or the iris (see below). It also was invoked to explain the dissociated tonic pupil syndrome (see Chapter 24). tively affected by a syphilitic toxin, and they were thus damaged, leaving the near-vision cells intact. (3) The pupilloconstrictor nucleus was assumed to be divided into two discrete subnuclei, one for the light reflex and the other for near vision; and in the Argyll Robertson syndrome the light reflex subnucleus alone was supposed to be damaged. In all of these theories the miosis was said to be caused by irritation or other pathologic influences from nearby diseased elements. These theories were later expanded to explain the common finding of normal accommodation and of exten- 19. Midbrain Syndromes: Argyll Robertson Pupils sive lid-close contractions of the pupils in such cases. Accordingly, the small-celled rostral oculomotor nucleus was divided into four subnuclei, serving first, the light reflex; second, the near-vision contraction of the pupil; third, the lid-close contractions of the pupil; and fourth, accommodation of the lens. There are serious objections against each of these hypotheses. First, the belief in a greater effectiveness of near-vision impulses, compared to those elicited by light, was merely a holdover from the time when weak light stimuli such as candles or gas light were used to test the patients' pupils. As soon as brighter light sources came into general use, it was found by all who made the comparison that, in fact, bright light is the more effective stimulus in many individuals (see Chapter 5). Besides, if the near-vision impulses indeed were stronger than the light impulses, the near-vision contraction of the pupil should never be lost selectively. But cases with "inverse Argyll Robertson pupils" were encountered. In such patients the near-vision contractions were abolished and the light reflex preserved. What is more, a patient could have the "inverse" syndrome in one eye and a classic Argyll Robertson pupil in the other (see Figure 32-11 ). Second, it is difficult to imagine a lesion that would pick out the iris light-reflex fibers or subnuclei for both eyes, leaving all other functions of the oculomotor nucleus intact. It is equally improbable that partial damage and an irritative condition of a minute subnucleus could continue without change for many years or decades; and the explanation of the miosis given in connection with these theories therefore cannot be maintained. Third, and most important, the assumption of two or even more separate cholinergic motor neurons and efferent paths for different kinds of pupillary constriction conflicts with the fundamental phy iologic rule that effector muscles are innervated by a final common motor path: all muscles of the body have only one kind of active motor innervation, and the coordination of contraction and relaxation of various muscles to produce different movements is the job of the central nervous system (see Chapter 9). None of the 'third nerve nucleus" hypotheses ever has been supported by a shred of experimental or pathoanatomic fact. In addition, beginning with Westphal's famous case in 1887 (Figure 19-22), pathologic studies have proven many times that Argyll Robertson pupils can be found in patients in whom the EingerWestphal nucleus is spared from injury (Tables 19-21 and 19-22). (b) The Efferent Third Nerve As already mentioned (see "Etiology"), some patients developed dissociated pupil syndromes, almost always unilateral, after an episode of third nerve palsy. The damage usually was caused by severe head trauma or basal aneurysms, occasionally by syphilitic basal meningitis or tumors. During the acute stage of these conditions the pupil was large and fixed; but some months or years later it became / 991 smaller, and in some cases quite small, or at least distinctly smaller than the normal pupil. The near-vision reactions were regained and could become brisk and relatively extensive while the light reflexes usually remained poor or absent. At first glance such cases appeared indistinguishable from the classic Argyll Robertson syndrome, and they were, indeed, mistaken for it. They were believed to prove that Argyll Robertson pupils could be caused by a lesion in the third nerve, and that the dissociated pupil syndrome is an intermediary step between complete iridoplegia and a normal pupil: upon partial recovery, the more powerful near-vision stimuli were said to become effective sooner than light stimuli, or the near-vision fibers were more rugged, or were placed axially in the third nerve, and thus were damaged less severely than the light reflex fibers. As already discussed above, these notions cannot be maintained. In addition, the resemblance between this phenomenon, later named "third nerve misdirection dyskinesia," and the Argyll Robertson syndrome is only superficial: in the Argyll Robertson syndrome the pupil constricts to near vision only; but in oculomotor misdirection it constricts in lateral gaze as well, whenever the globe is adducted. (c) The Ciliary Ganglion or Ciliary Nerves A large group of authors believed the lesion to be located in the ciliary ganglion or the short ciliary nerves. The dissociation between abolished light reflexes and preserved contractions to near vision was explained by assuming that the near-vision fibers running in the third nerve did not synapse in the ciliary ganglion but merely passed through it, so that cell damage there would not affect them; or by assuming that the near-vision elements were inherently more resistant to injury than the light reflex elements; or that the near-vision fibers circumvented the ciliary ganglion and reached the pupillary sphincter directly or by way of "episcleral ganglion cells" in the eye itself. These erroneous theories were proposed also to explain the dissociated tonic pupillary syndrome and are discussed in Chapters 3, 11, and 24. Marina (1896) often has been cited as having furnished anatomic proof of ciliary ganglion involvement in patients who had had Argyll Robertson pupils in life. But on closer inspection these findings were unconvincing (see Loewenfeld, 1969): the pathologic changes in these ganglia were only mild, and even in Marina's own material there were many patients without Argyll Robertson pupils whose ciliary ganglia were much more severely affected. In answer to Marina's claims, later investigators examined the ciliary ganglia of tabetic or paretic patient who had had Argyll Robertson pupils before they died (Table 19-23). The results were uniform: no damage at all was discovered. Since the pupillary syndrome thus can develop even when the ciliary ganglion remains entirely normal, the ganglion could not possibly be the seat of the responsible lesion (see also Chapters 3 and 24). 992 IV. Pupillary Pathology: Symptomatology (d) Damage in the Eye (1) Iris Damage-Iri damage ha been blamed for the Argyll Robert on yndrome, but it al o could not be the cau e: while many patient with Argyll Robertson pupil had iri damage, thi wa not a con tant feature, a it would have to be if the le ion respon ible for the yndrome were located there. The frequent coincidence of iri change and the pupillary yndrome i not upri ing, becau e both of the e defect often are caused by yphili . But there are many patient with Argyll Robert on pupil and healthy iri e , and many others with iri damage but without the Argyll Robertson yndrome. Furthermore, in the cla ic Argyll Robert on yndrome, the well-pre erved contractions to near vi ion and to in tilled phy o tigmine how that the peripheral n rve-mu cle apparatu is able to function (Guillery, 1 92; Levin ohn and Arndt, 1901; Orlando, 1936; Velter, 193 ). In thi connection, Dupuy -Dutemp was often cited A hql/1 as saying that the "special form of iris atrophy" he had described in 1905 was seen in all patients with the Argyll Robertson syndrome, and that it developed hand in hand with the pupillary impairment. This is, however, an exaggeration of Dupuy-Dutemp's descriptions: he had found this type of iris atrophy only in syphilitic patients with Argyll Robertson pupils but not in all of them; and he stated explicitly that the light reflex often was lost long before iris damage cou Id be seen (1905 1925). (2) Assumption of Intraocular Ganglion CellsPeripheral "nerve nets" with ganglion cells embedded in the choroid, the ciliary muscle, or the iris have been mentioned, off and on, for many decades, and some authors thought that such structures might be involved in the development of Argyll Robertson pupils (for example Marie, 1880; Oebecke, 1894; Magnani, 1904; Cosmcttatos, 1905; Hesse, 1912; Magitot, 1912, 1918; Parsons, 1924; Vuillaume, 1924; Bollack, 1938). But it B J I .{ Figure 19-22. Westphal's nucleus. The patient was a 44-year-old man with general paresis. He had had several episodes of unconsciousness, followed by paresis of his right extremities. At the time of admission he had begun to show mental signs. There were reflex and motor defects, including slight bilateral optic atrophy and complete paralysis of all extraocular movements. The pupils were fixed to light, but the near response and accommodation were present. On autopsy the large-celled components of the oculomotor nuclei were found to be degenerated, but a rostrally situated small-celled area was unimpaired. This group later was named the Edinger-Westphal nucleus. Westphal suggested that it probably served the intraocular muscles (with partial damage responsible for the absent light reflexes), while the large-celled part of the oculomotor nucleus normally innervated the extraocular muscles. A, nigrosine stain; 8, Weigert stain. J, atrophic nucleus; 2, median, small-celled area; 3, lateral small-celled area. These median and lateral intact cell groups were seen to merge in other sections of the preparation; 4, medial longitudinal fasciculus; 5, bundles of fine nerve fibers surrounding the median small-celled group and leaving the brainstem as root fibers to the third nerve. A net of fine fiber marks off the upper border of the nuclei. (From C. Westphal, Arch. Psychiat. Nervenkr., 18 [1887]:846) Table 19-21. YEAR AUTHOR Pathological studies on the oculomotor nuclear area in patients with Argyll Robertson pupils PATIENT 3 cases 1898 1880 Foerster Kahler & Pick 1885 Blanc n.s, 1885 Kaiser *l 0,,20 1887 1888 " O" 44 Westuhal Oppent,eim "I n II 1888 1889 1890 1891 ~itzka 1891 O" 48 15 I-~ case case CO:-IDITION n. s. vascular thromb. n.s, acute polioence- nhalomvelitis tabo-oaresis tabes (congcn ) 11. s. ,ru enheim Boetti2:er case n.s. tabes O"' 62 tabo-oaresis Boedecker ca:,C' Siemer ling 9 1892 1892 1893 Boedecker Siemerlin~ ~ .rn O" :iO Kostcnitch 1893 Boedecker " " " " EXTRAOCULAR 130 n. 1 MUSCLES PUPILS normal OU normal normal normal OU OU OU L<R AH posterior 30 nuclei damaged anterior oart snared anterior part intact disturbed anterior end of oculomotor normal n.s. lesion WE <Troun snared n.s. \VE t.oToun intact \VE CTroun intact Daralyzed chronic progressive oohthalmon!e<Yia L paralyzed R normal OU immobile OD 3 mm. 1 tabo-oarcs is general paresis AROU ARuu disturbed L congen1fiil ptosis <...)'T ;j4 ,._,_,.::, 1ues small, O" =>2 variri.ble pareses O" 48 acute alcoholic: polyencephalitis genera1 paresis unmobilc to liQ"ht; near n.s. immobile to light reacts to near OU unmobile R medium, general paresis normal R ophlliilmoplegia AR chronic ophthalmoolegia disturoed H = L; n GO 11. palsy 9 ~ 20 1~93 Zeri O" 3-1 acute alcoholic nolvcnccuhalitis tabes lb9U Cassirer #1 O" 42 tabcs 1:-trge, immobile " " //2 0"-1<1 9 44 tabes L>H; immobile OU H - L; maxunal size: " H RAR L limited L immobile uatient Schiff " ,. ., 6G tubes H <L, large; O" 40 L)H, Siemerling ry,'~f; ~ .)2 0,, 39 ccrebro-\·ascular disease tabo-oaresis general pares is veneral naresis general pares is Boedecker " •-1 u:; O":J7 " 09 O" " " .., case •4 " ¥6 O" j~ vr .. , O" -16 CY" lo ,j Had \'. rnu1 1903 Juliu!::iburger & Kaplan C:1ss11·er & Strauss .'.\Iarma Majano 1903 Xaka 1905 Sicmerling 1901 *:J 1905 Tsch1tlda ·~1 *4 " 1909 1918 #a " Orzechowski Brouwer 1920 1924 Frank •5 Warkany •-1 " " " " tabes cases O" 4h l:!enerai ua.rcs1s general paresis case v5 general oaresis n1orphine aaaict ~ case case O" 47 ~ 43 0 ? ? 6-1 ., n.s. tabo-naresis tabcs " "4 ? 58 tabes 115 ? 59 ? 69 4 cases " " !16 " ~2 " 1'4 ff5 Ilberg mgvar From Loewenfeld, ~: 56 O" 54 CY' Ul 0,. f/3 " ~~ Survey 11. S, taues tabcs vascular disease C~S lues general oaresis lues tabcs tabes merlium large, ophthalmoplegia OU immobile OU immobile OU verv noor vision R immobile L n1iotic AH H immobile LAH H)L, (blind) WE group spared \VE groups spared; basal 3° nerve drunarre, esneciallv L for WE group marked damage, except fibers lost WE •-row>s snared entirelv destroved de<"eneration /WE o-roup least) but efferent \VE group preser\·ed, L normal third nerves da.mag"ed H much degeneration L less dee-eneration H ophihalmoplegia both WE groups It ophthalmoplegia intact L normal immobile ve1T uoor to lii:!ht OU bilat. ouhthalmoule'1"ia n 3o n. -,,a1s,, limited OU WE .-rouos sli'1"htly damaged L Alt n.s. H. third ner\·e palsy L normal \VE lfrolloS well orcse i·ved \VE (!l'QUUS intact small softenin,r in area fl. :JOn. (foscicular) atrophy L normal; both WE groups intact AHOlJ normal \VE groups normal 11.S w ..: Vrouns normal \VE groups noi·mal immobile to li'1"ht (blind) maximal, immobile R immobile OU H s1nall, poor to light L immobile to lir£ht L ptosis tvpi.cal AH OU normal morphine miosis; minimal to liQ'ht;noor to nea R ophthalmoplegia R 3° &4° nuclei destroyed, L imoaired reacted n.s. L middle nart of 3° nucleus destroved both 30 nuclei damaaed (not destroved) \VE ,rroun intact normal nuclei including: \VE e:rouos OU immobile is 1mp:1.i1·ed orol!ressl\·e onhthal. onhthalmonle'1"ia ouhthalmonlerria AROII L>H; immobile hemorrhages m area 01 octuomotor but cells intact nucleus R damage to both oculomotor nuclei, worse than L; R efferent fibers destroved R Jess than L nuclei severely damaged, WE intact, but 30 n. root fibers damaged wt group normal, out 1asc1cu1ar 30 n. fibers deo-enerated WE group intact, Out 3° nerves involved in basilar meningitis especia11y anteriorly; fascicular impaired, disturbed impaired immobile OU n.lmost 1mn1obilc miotic WE group spared both WE nuclei intact, but L Jo nen·e (efferent) damage nuclear damarrc, but WE group spared -WE group intact total onhthalmonle<>fa immobile s1nn.ll R<L; AR uu L immobile R noor to lilrht & near 11 11 immobile,AR OU tetanus n.s. tabo-pares 1~~8 19:l0 tabo-parcsis O" 3U 6-1 Lenz " general paresis and alcoholic g-cneral oaresis sv inilis alcohol general uarcsis i!eneral uaresis ? l'2 Lenz 1/1 " paresis #2 Uchida,u___ 1930 51 9- general " 1927 ",, ? " " P!1negrossi " 1898 189U >/2 almost 1 side immobile 9 " 10~8 tabes Rossolimo " 1~96 •J optic atrophy; OU was bl ind limited we group intact immobile OU, H>L OS blind med itun size, reactive Kaiser nucleus \VE P-roun intact immobile AR NUCLEI except WE !!rouo to \VE grouo oara!vzed OS large, 1895 " intact comnlete loss tnbo-parcsis 49 & OU CNS lues 62 L miotic *2 all oaralvzed disturbed disturbed all oaralvzed immobile to li2'ht OU immobile to lhrht OU normal OU miotic AH immobile OU miotic !PATHOLOGY OF OCULO"'10TOR to light OU \VE ,TrouiJs intact ophthalmoplegia R limited L :JO out nerve palsy R li1nited in1oaircd n.s. R slow con tr. to nea1· L <R; immobile to in & out R internal and sup. Jioht OU rectus narcsis miotic, immob. to liuht n.s. R>L; AH OU n.s. iJnmohile to lil7ht OlI n.s. noor or immob. to li~rht n.s. imn1obile to lirrht normal unequal, ahnost fLxed n.s. miotic AR oc; normal miotic AH OU norrna.l L < R rniotic; AR l ?\ naresis H int. l'CC. medium, almost fixed normal ~ 7[1 tabes, arterioscl. 35 taues 58 L large; mt. ophtha!. ll 2.5 mm .. AR 0,- CXS lues large, case tabes unilate rnl AH Ophthal. 14(1969):199-299 immobile OU normal n. s. n.s. except ant. pn1·t; \VE groups normal WE group damaged \VE groups normal slight damage to WE group \VE 1!T0uos normal \VE Q""t·ouosslhrhtlv damaged \VE rirouns normal damaie to rostral small-celled area IVEaamao'ed but not destroyed sJi.,ht de2encration in WE group on1e damage in most rostral small-celled area and fibers leading to it; hard to interpret because of terminology used (no illustrations); belim·cs sphincter nucleus to be the / the "frontal nole of main nucleus" nuclei destroyed \VE groups intact The findings show that (l) The pupil remained normal in cases with extensive damage to the oculomotor nucleus if the small-celled subnucleus (Westphal-Edinger) was spared. (2) In most patients who had had Argyll Robertson pupils in life, this subnucleus was intact; few of them it was damaged, b~t in no case was 1t entirely destroyed. (J) When 1t was destroyed the pupils were relatively large and fixed to all stimuli. rostral in a n.s. • information not given; R • ri~ht; L = left; AR• Argyll Robertson syndrome; WE• Westphal-Edinger nucleus *l ~ later misinterpreted by ~ach as WE nuclei destroyed," but author reported that most anterior part intact • :2: later misinterpreted as AR pupils, WE nucleus destroyed," but patient was blind, pupils inrnobile. • *J later misrepresent~d as "good light reflex, absent WE nuclei." * 4: m!sinterpreted as ,,good light reflex, not a trace of WE nucleus remaining," but was only dama ed in case histor 5 misrepresented as WE nuclei degenerated," but were only damaged; last clinical observation ~ months before de~t = 993 994 I IV. Pupillary Pathology: Symptomatology Table 19-22. Additional pathologic studies of the oculomotor nuclear area in patients with Argyll Robertson pupils YEAR A 1 1 1 3 1 5 1 5 1 7 1 7 1 7 1 H 1 9 l~R9 1 89 1 89 1 89 1 9 1 9 1 9 1 90 1 91 1 91 Wernicke v. Gudden Darkschewitsch Edinger Moeli Ross Thomsen Rnitzka Blocq & Onanoff Darksc hew its ch Edini:wr lVIoeli Perlia Schlitz Westphal Uhthoff Brasch Schlitz THOR YEAR AUTHOR YEAR AUTHOR 1892 1892 1893 1894 1897 1898 1898 1899 1900 1900 1901 1903 1904 1905 1905 1905 1905 1905 1911 Eisenlohr Stuelo Uhthoff Schirmer Bernheimer v. Rad Schlitz Buchholz Harris Raecke Bernheim er Schulte Alzheimer Levinsohn Marburg Monakow Reutsch Woltlir Bumke 1913 1919 1919 1919 1920 1920 1920 1921 1922 1926 1927 1927 1931 1936 1937 1949 1950 1951 1954 Stargardt Buzzard & Greenfield (e) Bramwell (e) Lhermitte (el Souques & Bertrand (el Lhermitte (e) Redlich Folk (c) Hermann (e) Peter Jaensch Jaensch Cardona Lenz SavitzkV & Rangel! Schwab & al. Kyrieleis From Loewenfeld, Survey 0phthal. 14(1969):199-299 (el= patient had epidemic encephalitis. Table 19-23. YEAR Anatomic examinations of ciliary ganglia in patients who had had Argyll Robertson pupils AUTIIOR 1910 1911 Marinesco Thomas 1912 1914 1920 Thomas Sala Rizzio 1922 1936 Wilbrand Orlando PATIENTS & Minea & Saenger From Loewenfeld, Survey 0phthal. 9 tabetics 2 patients ANA TOl\IIC FINDIKGS with AR ouoils with AR pupils 2 tabetics with AR pupils oatients with AR syndrome 8 naretics with AR ouoils 2 paretics with immobile pupils 9 controls of srmilar age tabetics with AR pupils 15 patients with AR pupils no damage in ciliarv ganglion not the slightest degeneration in ciliary ganglion, its roots or ciliarv nerves ciliary ganglion and nerves entirely normal majority of ciliary ganglion cells normal no damage in ciliary ganlion cells, fibers, } co~~ctive tissue, ganglionic roots, ciliary nerves or iris nerves no pathology in ciliarv ganglion ciliary ganglion and ciliary nerves intact 14(1969):199-299 has been established quite firmly that, aside from stray ciliary cells, no cholinergic motor cells exist within the eye (see Chapter 1). (3) Vascular and Mechanical Theories-Occasionally the ciliary muscle and iris vessles were held responsible, directly or indirectly, for the Argyll Robertson dissociation. Thus, Knies (1893) and Schrnidt-Rimpler (1898) suggested that the near-vision contraction of the paralyzed iris was brought about by an increase of blood squeezed into the iris vessels by the contractions of the ciliary muscle when the patient looked near. Others have mentioned "nutritional defects" or "local metabolic changes" of the iris (Schwab, 1931; Vidal and Brodsky, 1943). Such "peripheral" theories have later been expanded (Langworthy and Ortega, 1943; Apter, 1954; Tarashi and Tosarelli, 1961; and especially Poos, 1949, 1950). Stripped of their verbosity and secondary assumptions, these hypotheses can be summarized as follows. The iris vessels were thought to be diseased and, secondarily, the iris nerves degenerated, while the iris muscles continued their "automatism" (Poos) or became "very rigid" (Langworthy and Ortega, Apter). Loss of light reflexes resulted from denervation of the sphincter, and miosis from denervation of the dilator (Poos) or from "inertia of elastic properties of the blood vessels and radial muscle fibers" (Langworthy and Ortega). The still active near-vision reactions were supposed to be the purely mechanical consequence of ciliary muscle contractions: the movements of this muscle were said to push the iris root forward and toward the center of the pupil and to lessen "tension" of the radial iris fibers sufficiently to cause pupillary constriction. I 995 19. Midbrain Syndromes: Argyll Robertson Pupils Table 19-24. The lesion responsible for Argyll Robertson syndrome assumed to be located in the intercalated (midbrain) neuron YEAR AUTHOR LOCATION OF LESIO YEAR AUTHOR C/J :::i '" C, LOCATION structure E named "' C ,an~ 1906 1906 1907 1910 1911 1911 1912 1913 1918 From Loewenfeld, Survey Ophthal. named 0 0 Linstow Wernicke Hempel F"<irster Erb Jackson Raehlmann Hirschber.,Moeli Ross de Watteville Westphal Hope Magnus ;\lendel Jessop Seggel Turner Gowers Knies Baas Zeri Hoche Lewis Pineles Goldscheider v. Leyden !.z Goldscheider Schmidt-Rimoler Bernheimer Schwartz Bechterew Deierine Harris Probst Marbure: Harris Schwartz V Monakow Ferrier Posey & Spiller Bumke Weiler Bailey & Jelliffe Bumke Winaver Behr Krliger structure "' -0 -0 1 67 1 72 1 76 1 77 1 0 1 0 1 0 18 1 18 7 l!:87 1887 1887 1888 1888 1889 1891 1891 1892 1893 1893 1895 1895 1896 1896 1896 1897 1897 1897 1898 1899 1899 1900 1900 1900 1900 1903 1904 1904 OF LESIO Cl) :::l + Meynert's fibers + + 1918 1922 1922 ,-,z., coll icular area + + + + + + + + l\Ieyne rt' s libers + 1924 1924 1924 1924 1925 1925 1926 1927 1927 1927 l,-,LO close to 3° n. nucleus :\levnert's fibers oeriaqueductal grey + close to 3° n. nucleus Meynert's fibers periaqueductal grey + J\levnert's [ibers + + periaqueductal grey + near 3° nerve nucleus near 3u nerve nucleus + + endings lo 3v nucleus + near 3v nerve nucleus l\Ieynert's fibers near 3u n. nucleus oeriaqueduc·al grey + endings to 30 n. nucl. + 1928 1928 1929 1930 1930 1930 1931 1931 1931 1933 1933 1933 1934 1935 1935 1935 1936 1936 1936 1937 1938 1938 1939 1942 1944 1947 l ::l;:>l endings to 3u nucleus + + + endings to 3°n. nucl. + 1952 1956 1956 1957 1958 1958 1961 Lutz Redlich Ricaldoni n.uw1and Bramwell Parsons Paton WarKany Behr Kalk Boente Herrmann Terrien Wilbrand & Behr Marque"z Soiegel Stern Lenz Belloni En.,-el Ingvar Bing Globus Gifford & Meyer Mc Andrews Soiegel Merritt & Moore Schaeffer Hehr Ceni Scala & Spiegel Gabriel Jaensch Scala & Spiegel Burki Garcin & Halbron Rea Rocha Meesmann Fuchs Walsh Doe:.,-art Ford Cogan Lowenstein Bonnet Passow Sorsby Huber close to 3° nerve nucleus periaaueductal grey area around aqueduct + periaaueductal grey near 3un. nucleus after central decuss. , near 3°n. nucleus fibers encircling central grev + endings to 3v nerve nucleus near 3o nerve nucleus fibers to 30 nerve nucleus endings to 3u nerve nucleus + periaqued. grey near 3° nerve nucleus l\leynert s noers close to 30 nerve nucleus endings to 3° nerve nucleus fibers entering 3° nerve nucleus orenuclear fibers entering 3° nerve nucleus pineal recess endini:rs to 3o nerve nucleus endings to 3o nerve nucleus + vicinitv of 3o nerve nucleus synapse to 30 nerve nucleus rostral to 3° nerve nucleus periaqued. grey rostral to 3°n. endings to 30 nerve nucleus nucleus + near 3°n. nucleus I beyond near 3° ne eve nucleus endings to 3° nucleus synapse to 3° nucleus oust. comm. + + .,. rostral to 3u nerve nucleus tloor 3° ventricle, near post.comm. close to 3° nucleus surround~ sphincter nucleus near 3u nerve nucleus + vicinity of tectum rostral and close to 30 nerve nucleus sup. colliculi or post. commissure endings to 3o nerve nucleus probably i:1retectum periaqued. grey, synapse to 3°n. nucleus 14(1969).199-299 These fanciful hypotheses conflict with facts already mentioned, such as the absence of discernible iris damage and the prompt and vigorous reactions to instilled drugs in many patients with Argyll Robertson pupils. Moreover, these theories would leave unexplained all cases with miotic pupils fixed to light and to near vision but with normal accommodation. Why would contractions of the ciliary muscle not move these pupils also? Finally, it can be seen plainly (when viewed with the slit lamp) that in patients with Argyll Robertson pupils the pupillary sphincter does constrict during near vision, while both the ciliary and the pupillary iris zones widen. 4. Damage in the Intercalated Midbrain Neuron . As shown in the preceding sections, the lesion responsible for Argyll Robertson pupils cannot be situated in the _spinal cord, the afferent path of the light reflex in the optic nerve or tract, the sphincter nucleus, the efferent path via th~ third ~~rve, the ciliary ganglion and ciliary nerves, or m the ins. The central connecting neuron between the sensory and the motor arms of the reflex arc thus remains the only possible site. This conclusion has been_ reached many times (Table 19-24). In patients with a umlateral Argyll Robertson pupil the lesion must be 996 I IV. Pupillary Pathology: Symptomatology ituated beyond the central hemidecus ation of the light reflex path, becau e impairment before this decussation, ju t like le ion of the optic tract, would necessarily affect both pupil . The pupillary light-near di sociation is easy to undertand on the ba is of uch a midbrain lesion: the crossed and uncro ed pretectal light reflex fibers swing around the central grey, after partial decussation in the posterior commi ure, and approach the Edinger-Westphal nucleu from a ro tro-dor al direction. They thus could be involved in a le ion that would pare the near-vision fiber for the pupil ince these approach the nucleus from a more ventral direction. The cells of the EdingerWe tphal and the anteromedian nuclei-as well as the re t of the oculomotor nucleus and the efferent motor fibers leaving the nuclei ventrally-would remain unharmed al o ( ee Figure 19-23). This would explain why accommodation remains normal in patients with Argyll Robert on pupil , and why defects of extraocular movement are not part of the syndrome. (a) Experimental Evidence Dissociated pupil syndrome were produced in animals by denervation or by de truction of the pretectal neuron: Karplus and Kreidl (1912, 1913) cut both superior collicular brachia in cats and monkeys and observed that the light reflexes remained permanently abolished, while the pupils still con tricted when the animals looked near or when they tried to close their eyes against resistance. Similarly, Magoun and Ranson (1933, 1935) found extensive lid-do e contraction in cats with pupils fixed to light after bilaterial pretectal lesions; and Akimoto (1959) and Otsuka (1960) reported that the light reflexes were lost but "postural reflexes" 8 were preserved in rabbits after destruction of the posterior commissure. Finally, Akimoto and co-workers found (in rabbits) a tegmental pupilloconstrictor path not related to the light reflex arc: electric stimulation via electrodes situated in this fiber tract caused pupillary constriction, but no action potentials could be recorded when the animals' eyes were exposed to light; such potentials were readily obtained 8. These postural reflexes were movements <?f the eyes nasally and pupillary constriction when the ammals were placed on their backs. Figure 19-23. Connections of the oculomotor nuclei. The diagram B shows details of the midbrain area framed in A. The black, small rostrodorsal part of the third nerve nucleus corresponds to the Edinger-Westphal and anteromedian nuclei, as drawn by Warwick (see Chapter 3), the lightly stippled area to the rest of the oculomotor nuclei. Note the crossed and uncrossed pretectal light-reflex fibers that approach the nucleus from a r?st~o:dorsal direction (large black arrows), together_with central_ •~h1b1tory impulses (small black arrows). The pup1llary near-v1s1on and accommodative paths (darkly shaded arrow) and the efferent fibers leaving the nucleus (white arrow) are situated more ventrally. P.C., posterior commissure; Pt., pretectal area. (From I.E. Loewenfeld, Survey Ophthal., 14 [1969):199) when the electrodes were placed within the light reflex pathways. (b) Pathologic Evidence It has been said many times that no midbrain lesion was found in patients with Argyll Robertson pupils. This statement has, in fact, become the chief argument for rejecting a mesencephalic lesion as cause of the Argyll Robertson syndrome. But is it true? The answer to this question depends on what kind of damage was looked for. It is indeed true that no isolated, sharply outlined area of destruction has been found regularly in the same location in the midbrain of patients with Argyll Robertson pupils. It should B 19. Midbrain Syndromes: Argyll Robertson Pupils Table 19-25. Midbrain pathology in patients with Argyll Robertson pupils A. MOST CHARACTERISTIC YEAR AUTHOR 1 1852 1 63 1 67 1 67 1 80 1 :80 1 85 18 7 1 8 1 8 1 9 1 9 1890 1891 1891 1891 1892 1892 Vega Billod v. Lins tow Westphal Marie Mendel Blanc Thomsen Onnenheim Soitzka Mendel Moeli Boettiger Schiltz Siemer ling Boedecker Guillerv Siemerling + + + + + + + + 1 = granular FINDI 2 + + + + + + + + + + + + + + + + + ependymitis; 2 GS IT SYPHILITIC PATIE "TS WITH ARGYLL ROBERTSO YEAR AUTHOR 1 2 YEAR AUTHOR 1893 1893 1 94 1 94 1 97 1 98 1 98 1 99 1 99 1899 1900 1902 1903 1903 1904 1905 1905 1908 Uhthoff Westphal Binswanger Streitberger Boedecker Panegrossi Schulze Buchholz Julius burger & Kaplan Raecke SchUle Reichardt Schulte Alzheimer Rentsch \VolUlr Junius&Arndt + + + + + + 1911 1913 1919 1919 1920 1922 1923 192--l 1926 1927 1927 1927 1928 1929 1930 1936 1937 195-! 1962 Bumke Stargardt Buzzard & Greenfield (e) Bramwell (e) Redlich Spielmever Warkany Spitzer Uchida \Vilbrand & Behr Lenz Lenz II berg Jaensch Cardona Sasaki Bruetsch = glial proliferation; + + + + + + + + + + + + + + + + (e) = patient had encephalitis YEAR AUTHOR 1881 1887 1888 1889 1890 1890 1891 1892 1892 1895 1896 Wernicke Moeli Thomsen Schlitz Boettiger Uhtho.ff Schlitz Boedecker Eisenlohr Zeri Boedecker be added not been patients. found to Survey L Il + + + + + + + + + + + Ophthal. E YEAR 1 97 1897 1898 1898 1898 1900 1900 1903 1903 1904 1913 AUTHOR Siemerling & Boedecker Panegrossi Schlitz Schulze Ilarris Raeckc ?.Iaiano Schulte Alzheimer Stargardt L II + + + + + + + + + + E PUPILS 1 2 + + + + + + + + + + + + + + + + + + + + + + + + lethargica B. :MARKED PATHOLOGY IN PERIAQUED CTAL GREY A 'D S RRO ·Nm 'G AREA II= hemorrhage in acute alcoholic encephalitis; E = involved L= fiber loss in syphilis; encephalitis. From Loewenfeld, 997 / in lethargic YEAR A TIIOR 1921 1922 1924 1926 1926 1927 1927 1929 1937 19t>0 195-! Lhermitte Redlich Warkanv Folk Spitzer Peter Uchida Lenz Cardona Savitzh.-y & Rangell Sasaki L H E + + + + + + + + + + + 14(1969):199-299 parenthetically that such a discrete lesion has found anywhere in the nervous system of these Further, it is not true that the midbrain was be healthy in patients with the pupil syndrome. On the contrary, a great deal of pathology was observed in tabetic and paretic patients, especially in the region surrounding the caudal part of the third ventricle and the aqueduct. While the cells of the Edinger-Westphal nucleus usually were spared (see Table 19-21), the fibers surrounding them were thinned and interspersed with thick layers of proliferating glia. There was granular ependymitis along the ventricular walls, with subependymal gliosis up to complete obliteration of the aqueduct. There was severe fiber loss in the periaqueductal grey, and early and marked pathology of blood vessels (Table 19-25). Occasionally, dis- ease foci were seen in the pretectal area, in or near the posterior commissure, or in the fibers approaching the oculomotor nuclei (see, for example, Moeli, 1887; Spitzka, 1887; Westphal, 1889; Boettiger, 1890; Siemerling and Boedecker, 1897; Hermann, 1927; lngvar, 1930; Sasaki, 1954). In cases with epidemic encephalitis or with Wernicke's hemorrhagic encephalitis superior, the midbrain showed more severe changes than any other region of the brain, with vascular engorgement, perivascular infiltration, chromatolytic ganglion celJ changes, small hemorrhages, and glial proliferation. In patients with multiple sclerosis demyelinated plaques were found in the periaqueductal region (Uhthoff, 1890; Buchholz, 1899; Savitzky and Rangell, 1950; Schwab et al., 1951). Finally, in patients with tumors or vascular lesions 998 I IV. Pupillary Pathology: ymptomatology affecting the ro tral midbrain, the le ion was known to be ituated in the area of the central light r flex neuron; and ome of these patients had mi tic di ciated pupils that re em bled the Argyll R bert on yndr me in all re pect . It can be een then, that a large number of patients with rgyll Robert on pupil or with clo ely similar, di iated pupil yndrome did have le ion known to b ated in the ro tr -dor al midbrain, and that ten i e, diffu e pathology in thi area was the rule in pati nt wh had died from tabe or from general pare i . In contra t, the general tatement in the literature that there wa no midbrain damage in the rgyll R bert n yndrome were not upported by case rep rt f actual patient with the pupillary syndrome and with a healthy midbrain. It h uld be remembered that the number of pr tectal pupillary fiber cannot be very large, judging from the number of neurons in the efferent reflex path. When thi small number is c mpared with the enormou ma of fibers running in the variou a cending and descending tract f r the entire body, which all traverse the narrow pa age of the midbrain, it becomes clear that a relatively mall le ion must suffice to interrupt the pupillary pathway. In addition much damage probably was missed in the older pathologic tudies, ince the Marchi technique wa used to demon trate fiber degeneration. In patient with tabe or general paresis, little myelin degeneration could be expected becau e the de tructive process was so far beyond the acute tage. In such cases, nerve fiber stains and tain for glia demonstrated marked pathology which had not been found with the Marchi method (Schulze, 1898; Harris, 1900; Levinsohn, 1990-1905· Warkany, 1928; Sasaki, 1954). (c) Clinical Evidence Other facts also indicated a central location, such as the preponderance of bilaterality of the pupillary syndrome, the frequent co-existence of Argyll Robertson pupils with (nuclear) extraocular paresis, and the common combinations of an Argyll Robert on pupil in one eye and iridoplegia or internal ophthalmoplegia in the other eye. Moreover, it was not unusual to see a miotic Argyll Robertson pupil develop to mydriatic iridoplegia in a later stage of the disease, and in such cases corresponding lesions were found in the oculomotor nucleus (Guillery, 1892; Baas, 1894; Levinsohn and Arndt, 1901; Holden, 1905; Duverger and Redslob, 1923; Bielschowsky, 1925). In epidemic encephalitis and in Wernicke's disease midbrain signs such as ptosis and impaired eye movements were seen with outstanding frequency. It would not be reasonable to as ume that in all these patients the extraocular and intraocular palsies due to midbrain damage were merely coincidental and that a separate lesion for the Argyll Robertson pupil was located elsewhere. A number of authors have remarked that the midbrain pathology found in syphilitic patients with Argyll Robertson pupils was quite similar to the tabetic le ions in the spinal cord that were responsible for loss of deep tendon reflexes: in the cord, also, there was degeneration of reflex collaterals with glial proliferation, while the motor ganglion cells were not destroyed (Harris, 1900; Bumke and Trendelenburg, 1907; Wilbrand and Saenger, 1922; Paton, 1924; Behr, 1925; Hermann, 1927; Lenz, 1929; Bing, 1931). It has been sugge ted that only aparticularkind of disea e process, such as chronic inflammatory or toxic condition , could produce this type of damage. The pupillary fibers were thought to have a special affinity for a syphilitic toxin, or the toxin could penetrate the central grey substance especially well (Wilson, 1921; Bramwell, 1924). The blood-brain barrier was reported to be practically nonexistent in the periaqueductal region (Gulotta, 1968), which would encourage penetration of toxic substances and seepage of fluid from the blood into the brain tissue. Others pointed out that the area of the oculomotor nucleus lies at the boundary zone between the carotid and the basilar vascular beds; and since midbrain vessels arc end arteries, there would be no collateral circulation. Such areas, supplied by the most peripheral branches of the vascular tree, would be most vulnerable to disturbances of the blood supply. It is possible that in individual cases one or the other of these factors may play a dominant role. ln general, however, it appears that any kind of lesion- infectiou , toxic, traumatic, inflammatory, degenerative, or one cau ed by simple pre sure-will bring about the di sociated pupil syndrome when it interrupts the light reflex fibers just dorso-rostral to the oculomotor nucleus but leaves intact the near-vision fibers, the sphincter nuclei, and the efferent pupilloconstrictor path to the iris. 5. Mechanism of the Miosis (a) Sympathetic Paralysis Miosis was one feature of the classic Argyll Robertson syndrome not produced in experimental animals with lesions in the pretectal light reflex neuron. For this reason some authors dismissed these experiments as not pertinent. Others, who did believe that the light-near dissociation was due to a central interruption of the light reflex arc, thought that additional damage in the spinal cord caused the miosis, by affecting the sympathetic supply of the iris dilator muscle (Table 19-26,A and B). This widely held opinion had its roots in the historical facts that the dissociated pupil syndrome was first discovered in patients with tabes dorsalis and that Argyll Robertson had given it the suggestive name of "spinal miosis." Later, when it became clear that the sympathetic outflow was controlled by more rostral portions of the brainstem, the site of the assumed sympathetic lesion was moved upward into the medulla or the midbrain (Table 19-26,C). The concept of a midbrain lesion was especially attractive, because it eliminated the need for two separate lesions to abolish the light reflex and pupillodilation. It was said 19. Midbrain Syndromes: Argyll Robertson Pupils Table 19-26. Miosis in Argyll Robertson syndrome considered due to sympathetic impairment A. PERIPHERAL SYMPATHETIC FIBERS, OR SITE YEAR AUTHOR YEAR AUTHOR 1854 1858 1863 1863 1864 1867 1868 1868 1873 1874 Willebrand Richarz Billod Wells Duchenne Rinecker Magnan Poincare & Bonnet Fetrow Mobeche 1876 1878 1884 1886 1886 1892 1895 1899 1900 1905 Hempel Doutrebente Althaus l\Ioebius Schille Krafft-Ebbing Collins llirscJll Harris Grasset B. SYMPATHETIC DEFICIT 1 OT SPECIFIED (partly) YEAR AUTHOR 1906 1906 1920 1923 1926 1927 1927 19zts 1935 1938 Bertozzi Posey & Sp ill er Landolt Bramwell Danis & Coppez Boente Lafon Bernauct Myerson & Thau Peyret IN THE SPINAL DUE TO LESIO CORD YEAR AUTHOR YEAR AUTHOR YEAR AUTHOR 1840 1863 1864 1864 1864 1866 1867 1868 1869 1877 1878 1878 Stilling Wells Remak Stell wag Voisin ITutchinson Cvon Voisin Robertson Foerster Hutchinson Raehlmann & Witkowski Erb Gesenius Leber Stewart Charcot Erb Mendel Raehlmann (partly) Hirschberg Rieger & Forster Senator Bechterew Parinaud Berger Michel 1893 1893 1895 1896 1897 1897 1898 1898 1898 1898 1&98 1898 1898 1899 1899 1899 1899 1899 1899 1900 1900 1900 1901 1901 1901 1902 1902 1903 Gowers Knies Baas Lewis Heymann Hudson Bach Gaupp Kauffmann Liebrecht de Schweinitz (*1 Wagner Wolff Bach Marina Schwartz (partly_:') de Schweinitz Wagner & Stolper Wolff Gliksman Onuf & Collins Just Schaffer Wolff Pierre-Marie Wolff Reichardt 1903 1904 1904 1905 1906 1906 1907 1907 1908 1920 1921 1922 19Z3 1924 1925 1931 1937 Torkel Donath Reichardt Reichardt Bach Mtillerleile Brassert Wunderlich Gaupp 1te1cnarat Elminger Weiler Siebert Behr (partlyx\ Dejerine & Regnard Roussy & Cornil Aobab Ketchum Rowland Fuchs Behr(") Holzapfel Desplanques 1958 1959 1961 Sorsby Guillaumat Huber 1879 1879 1879 1879 1880 1880 1880 1880 1881 1881 1881 1883 1884 1888 1890 C. SYMPATHETIC DEFICIT DUE TO LESION ROSTRAL l;:,vo 1910 1910 1912 1913 1920 TO THE SPINAL & al. CORD YEAR AUTHOR SITE YEAR AUTHOR SITE 1858 1876 1877 1879 1880 1A82 1886 1889 1893 1896 1914 1918 1923 Oirle Hempel Vincent Erb Raehlmann Moebius Salgo Berger Gowers Lewis Antoni Lutz Rowland CNS medulla brain congestion rostral to cord cortex or medulla midbrain or medulla cortex medulla midbrain tegmentum midbrain tegmentum frontal lobe midbrain te=entum medulla 1927 1931 1933 1934 1934 1935 1936 1936 1947 1948 1954 Hartmann Holtz apt el Merritt & Moore Editorial, J. AMA Scnaetter Gowers Frey Gabriel Walsh Merritt & al. SkorodUIUova medulla medulla midbrain tegmentum midbrain tegrnentum penaqued: midbrain midbrain tegn1entum wall of ootic recess midbrain tee:mentum midbrain tei:rmentum midbrain tegmentum level not soecified From Loewenfeld, Survey Ophthal. 14(1969): 199-299 / 999 1000 / IV. Pupillary Pathology: Symptomatology that a single pretectal lesion could include both the light reflex fiber and the de cending pupillodilator tract. The a sumption of a sympathetic defect in the Argyll Robert on syndrome has, however, never been supported by experimental or clinical evidence, and there are everal good reason to dismiss it, as already mentioned in the de criptive parts of this chapter. (1) The Argyll Robertson miosis often is much tighter than can be explained by sympathetic denervation. (2) Except for miosis, not a single sign of ympathetic paraly is is een in these patients. (3) Pupillary dilation to psycho ensory stimuli and to cocaine are not impaired in many patients with the cla sic yndrome. . (4) ~o anatomic damage was found at autopsy in penpheral ympathetic nerves or ganglia of patient with Argyll Robertson pupils. Similarly, the_ cervical cord in ome of these patients was entirely unharmed; and in tabetic patients with cord damage the dorsal columns usually were impaired, but not the cells of origin of the sympathetic fiber in the lateral horn, nor their efferent path by way of the ventral roots. (5) A lesion in the lateral medulla will indeed cause ocular sympathetic paralysis (Wallenberg's synJrome) but not Argyll Robertson pupils. (6) Finally, a lesion in the midbrain tegmentum that would include the descending pupillodilator fiber to both eyes would have to very large, since the e pathways run far laterally in this area and not in or near the central grey, as has been claimed (see Chapter 6). (b) Sphincter Contraction It is quite certain that the miosis in the Argyll Robertson syndrome is due to contraction of the pupillary sphincter. As already mentioned, the miosis in this syndrome is far more marked than the miosis due to sympathetic paralysis. Furthermore, the small Argyll Robertson pupil enlarges when the ciliary nerves or the sphincter muscle are subjected to pressure and consequent ischemia, as in acute attacks of glaucoma (Lutz, 1918). The miosis also disappears when the patient dies (Lutz, 1918; McGrath, 1932), or when the oculomotor nerve is injured by trauma (Lafon, 1909). Similarly, the pupils become large in later stages of syphilitic diseases of the central nervous system when the oculomotor nucleus is destroyed, or when the third nerve fibers are damaged by basal syphilitic meninigitis (Guillery, 1892; Baas, 1894; Levinsohn and Arndt, 1901; Holden, 1905; Duverger and Redslob, 1923; Lentz, 1936). Finally, Argyll Robertson pupils dilate well to atropine, unless the iris is damaged (see Table 19-10 and Figure 19-15). This proves that the miosis is due to parasympathetic activity; and since Argyll Robertson pupils fail to dilate in darkness as normal pupils do, this sustained, spontaneous cholinergic outflow is abnormal. How can such cholinergic action be brought about? As shown in Figure 19-23, a lesion just rostral to the Edinger-Westphal nucleus must intercept not only the light reflex fibers from the pretectal area but also the descending central inhibitory pathway from higher areas of the brain which approach the oculomotor nucleus in this region (Turner 1982; Schwarz, 1904; Lafon, 1909; Behr, 1923; Waardenburg, 1921; Lloyd, 1923; Bramwell, 1924;Fuchs,1924;Marquez,1924;Jaensch,1936;Lowenstein, 1956). Absence of central inhibition generally causes permanent spasticity in motor systems (spastic paralysis); and there is no reason why the pupillary sphincter should be an exception to this rule. Indeed, when lesions are placed in animals at the rostral border of the midbrain (cerveau isole), the pupils remain tightly constricted as long as the preparations are kept alive (Bremer, 1935; Spiegel and Scala, 1935; Claes, 1936; Keller, 1944; see Chapter 9). Similarly, the tight miosis in normal sleep and in deep narcosis is due primarily to loss of central inhibition and consequent contraction of the pupillary sphincter. It has been objected that spasticity of the sphincter muscle could not continue over many years (Rinecker, 1867; Erb, 1880; Berger, 1889; Bramwell, 1924; Scala and Spiegel, 1935); and that the pupillary sphincter, if it were spastic, could not be expected to contract further to near vision (Hempel, 1876; Erb, 1880; Althaus, 1884). But since spastic paralysis in other motor systems may last for long periods and, except in maximal contracture, spastic limbs may move further on appropriate stimulation, these arguments do not appear convincing. It should be added that in normal man and animals the pupillary sphincter is contracted during a good part of the individual's lifetime, that is, during sleep, and further constriction may be obtained by light stimuli. Lowenstein (1956) suggested that the miosis of Argyll Robertson pupils may be enhanced by the phenomenon of denervation supersensitivity, which has been shown to develop in central nervous structures as well as in peripheral ganglia and effector organs: the neurons of the Edinger-Westphal nucleus, deprived of their major afferent supply when the light reflex path is interrupted, may become supersensitive to cholinergic substances, and then they may respond by increased spontaneous firing to such substances; these may reach the pupilloconstrictor neurons from surrounding nerve centers, or, carried in the blood, from other sites. 19. Midbrain Syndromes: Argyll Robertson Pupils / 1001 F. Conclusions on Probable Site and Mechanism In summary, then, it appears clear that the hypotheses placing the lesion in (1) the cervical cord, (2) the third nerve nucleus, (3) the efferent third nerve fibers, (4) the ciliary ganglion or ciliary nerves, (5) the iris, or (6) special pupillary elements in the retina, optic nerve, or tract must be discarded, as none of them accords with the anatomic, physiologic, and clinical facts known today. By exclusion the only remaining possible site is the intercalated midbrain neuron which transmits light reflex impulses from the afferent pathways to the oculomotor nucleus. And this assumption is supported by ample pathologic and experimental evidence. As to the miosis in Argyll Robertson pupils, the theories involving a lesion in the sympathetic pathways to the pupillary dilator muscle clash with the fact that in most patients with this syndrome the sympathetic innervation of the eye remains intact. Moreover, it is not necessary to invoke a separate cause for the miosis because a midbrain lesion which interrupts the light reflex path just rostral to the Edinger-Westphal nucleus must also intercept the inhibitory fibers which reach this nucleus from more rostral sites. These fibers must be concentrated in this area in order to reach the small nucleus. And loss of central inhibition, as in all other motor nuclei, causes increased spontaneous firing of the pupillary sphincter neurons that results in tight miosis. The miosis may be enhanced by supersensitivity of the constrictor neurons, caused by their partial denervation when the light reflex path is destroyed.