- Email: [email protected]
Cyclic Oculomotor Paralysis*
AMBLYOPIA AND CONGENITAL CATARACT visual acuity in these children will be poor. Most of these patients had repeated needlings but some had linear extractions or even secondary removal of membranes. No rela tionship appears to exist between the type of operation and the final visual acuity. Of particular interest to me has been the patient who was successfully operated bilaterally and wore glasses continuously from the age of four months but in whom visual acuity could be corrected to only 6/30 at the age of eight years.
529
CONCLUSION Poor visual acuity following surgery for congenital cataract may depend upon the simultaneous presence of congenital ambly opia. Nystagmus is a frequent associate of con genital amblyopia and its presence predicts a probable poor visual prognosis. Visual acuity as good as 6/15 can occa sionally be obtained even in the presence of nystagmus. University Hospitals.
REFERENCES
1. Bagley, C. H.: Congenital cataracts. Am. J. Ophth., 32:411, 1949. 2. Carbajal, U. M.: A safe approach in surgery of congenital cataracts. Am. J. Ophth., 52:361, 1961. 3. Chandler, P. A.: Surgery of the lens in infancy. Arch. Ophth., 45:125, 1951. 4. Cordes, F. C : Surgery of congenital cataracts. Am. J. Ophth., 31:1073, 1950. 5. : Evaluation of the surgery of congenital cataracts. Arch. Ophth., 46:132, 1951. 6. : Failure in congenital cataract surgery. Am. J. Ophth., 43:1, 1957. 7. : Surgery in congenital cataracts. In Haik: Symposium on Diseases and Surgery of the Lens. St. Louis, Mosby, 1957, 8. : Linear extraction in congenital cataract surgery. Am. J. Ophth., 52:355, 1961. 9. Costenbader, F. D., and Albert, D. G. : Conservatism in the management of congenital cataract. AMA Arch. Ophth., 58:426, 1957. 10. Falls, H. F.: Developmental cataracts: Results of surgical treatment of 131 cases. Arch. Ophth., 29:210, 1943. 11. Gregg, N. M.: Congenital cataract following German measles in mother. Tr. Ophth. Soc. Australia, 3:35, 1942. 12. Jaffe, N. S., and Light, D. S.: Surgery of developmental cataract. AMA Arch. Ophth., 59:407. 1958. 13. Jones, I. S.: Needling of congenital cataracts. Am. J. Ophth., 52:347, 1961. 14. Kirby, D.: In Berens, C : The Eye and Its Diseases. Philadelphia Saunders, 1936. 15. Newton, F. H.: Congenital cataracts. Am. J. Ophth., 52:368, 1961. 16. Owens, W. C, and Hughes, W. F., Jr.: Results of surgical treatment of congenital cataract. Arch. Ophth., 39:339, 1948. 17. Wilson, W. A.: Congenital cataracts. AMA Arch. Ophth., 67:163, 1962. CYCLIC O C U L O M O T O R HERMANN
M.
B U R I A N , M.D.,
PARALYSIS*
AND M A U R I C E W.
V A N ALLEN,
M.D.
Iowa City, Iowa Among the rarest and most interesting forms of the paralyses of the third nerve is that which goes under the name of cyclic oculomotor paralysis, t In this condition some of the extraocular muscles over which * From the Neurosensory Center (Publication No. 9) and from the Departments of Ophthalmol ogy and Neurology, College of Medicine, State University of Iowa. The Neurosensory Center is supported by Program Project Grant B3354 of the National Institute of Neurolgical Diseases and Blindness, Bethesda, Maryland. Presented at the 98th annual meeting of the American Ophthalmo-
the patient has lost all voluntary control con tract spastically at more or less regular in tervals. The sphincter of the iris which is essentially nonresponsive to all physiologic stimuli, together with the paralyzed ciliary muscle, contracts synchronously with the ex traocular muscles. logical Society, Hot Springs, Virginia, May, 1962. t Walsh who has such a vast experience in the field of neuro-ophthalmology states that he has ob served only one example in a Negro boy shown at the New York Academy of Medicine.1
530
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN
We all know this condition from text books but few of us have actually seen it. The rarity of the condition and its pathophysiologic implications warrant the report ing of a case which we have had the oppor tunity to study. Before presenting this report it might be helpful to summarize some of the charac teristics of the cyclic oculomotor paralysis, as culled from the literature. Onset. In well over one half of the cases the condition was congenital or arose in the first six months of life. In four cases it could be reliably established that the oculo motor paralysis occurred many years prior to the onset of the cyclic phenomenon. There was no family history of either oculomotor paralysis or of the cyclic phenomenon with the exception of one case (Bonnet 2 ), where both mother and son were afflicted. No se vere illness preceded or coincided with the onset of the oculomotor paralysis. Degree of oculomotor involvement. In most of the reported cases the paralysis of the third nerve was complete, but in a few instances it was only partial, so far as the extraocular muscles were concerned. The pa tients could not raise the lid or adduct, ele vate or depress the globe. In the patients in whom the paralysis was not total certain of these movements could be performed to a degree. Pupillary responses to physiologic stimuli. The pupil of the affected eye did not re spond to light either directly or consensually, nor was there any response to convergence impulses or to sensory stimulation. Only Löwenstein and Givner3 found minimal pu pillary reactions in their patient by pupillography. This response was tonohaptic in nature. Structures involved in the cyclic phenom enon. The sphincter of the iris and most likely also the ciliary muscle were involved in every case. In a number of them (Aurand and Breuil,4 Fromaget,5 Levinsohn,6 Franke, 7 Paterson,8 Uhthoff,9 Stein,10 Hicks and Hosford, case l 11 ) these two muscles were the
only ones affected. Next in frequency was the levator muscle of the upper lid, and oc casionally the medial rectus muscle took part in the cycles of spasm and relaxation. Character and time course of the cyclic phenomena. In the phase of relaxation the upper lid hangs flabbily over the globe which is deviated outward and downward. The pu pil is dilated, accommodation is relaxed. This phase lasts for one to three minutes. In the full-blown cases one notes toward the end of this period twitching movements of the upper lid which then suddenly and smoothly rises to give the lid fissure its nor mal width. At the same time the mydriatic pupil constricts to a diameter of one to three mm., the eyeball moves to the midline and there is a spasm of accommodation. This is the spastic phase which may last from 30 to 100 seconds, depending on the case and the circumstances. Then there are again a few twitching movements of the upper lid, the eye suddenly turns out, the pupil dilates and the lid returns to its ptotic position. The cy cles of spasm and of relaxation repeat them selves with great regularity. As has been stated, in some cases only the pupil and the ciliary muscle are involved in the spastic cycle. It has also been noted in one or two instances that the phase of relax ation may last considerably longer on some days than on others. Effect of impulses to perform eye move ments on the cyclic phenomena. Eye move ments—or volitional impulses to perform an eye movement where such a movement is impossible owing to the paralysis—do not of themselves cause the appearance of either the spastic or the relaxed phase. But it has been established that certain intended eye move ments favor one or the other phase, prolong ing it at times indefinitely, or shortening the contrasting phase. Thus, adduction, or intended adduction, as well as convergence and fixation with the affected eye, favor the spastic phase, whereas abduction favors the phase of relaxation. Bielschowsky,12 Salus13 and others, have
CYCLIC OCULOMOTOR PARALYSIS
noted that depression in the spastic phase results in a pseudo-Graefelike phenomenon. In the phase of relaxation no such occur rence is observed when depression of the eyes is attempted. Where it was looked for Bell's phenome non was found to be present, although the patients were unable to elevate voluntarily the affected eye. In two instances (Levinsohn,e Krämer 14 ), the Westphal-Piltz reac tion (orbicularis phenomenon of the pupil) was positive. Influence of drugs on the pupillary cycle. Instillations of atropine caused maximal di latation of the pupil of the affected eye and abolished the pupillary cycle. Selinger15 re ported that his patient complained of rhyth mic pain in the eye with the use of pilo carpine, coinciding with the spastic phase, evidenced by contractions of the levator of the upper lid, although the pupillary cycle it self was abolished. Groethuysen10 mentioned similar pain with the use of eserine. He found that instillation of this drug, while producing a miosis of 1.8 to 2.5 mm, did not prevent the pupil from contracting fur ther during the spastic phase. Cocaine did not stop the cycle but caused dilatation of the pupil which did not constrict as much in the spastic phase as it did without the use of the drug. Adrenalin had no effect on either the width of the pupil or the pupillary cycle. Influence of sleep and anesthesia on the cyclic phenomena. Axenfeld and Schiirenberg" noted in their patient that during sleep the spastic phase occurred every two to five minutes, whereas it occurred in the wak ing state every one to three minutes. In three cases the phenomenon continued dur ing sleep (Bonnet,2 Kubik,18 Mak van Waay 19 ), but in Mak van Waay's case the spastic phase appeared to have been short ened and the relaxed phase considerably pro longed. In another case the eye was closed during sleep, but there were irregular twitches of the upper lid (v. Hippel 20 ), in two the cycle was abolished (Selinger,15 Uhtoff 9 ). It is of interest that it was noted
531
in two patients that the pupil could not be observed during sleep, because the patient slept extremely lightly (Uhthoff,9 Löwen stein and Givner 3 ). Uhthoff9 stated that the cycle was also abolished in general anesthesia. Influence of manipulations of the circu latory system on the cyclic phenomena. Nei ther slowing down or acceleration of respira tion (Aurand and Breuil 4 ) or an increase in pulse frequency to ISO (Aurand and Breuil,4 Groethuysen16) nor compression of the com mon carotid artery (v. Hippel 20 ) had any effect on the cyclic phenomena. CASE REPORT*
A white boy, born April 9, 1957, was seen by one of us (H. M. B.) on July 1960. He was the first child of the parents who stated that the preg nancy and delivery were normal. The boy's birthweight was nine pounds 11 ounces. The parents noted nothing wrong with the boy's eyes but the pediatrician mentioned that the right eye would not turn in. The right lid also appeared at first normal to the parents. During the first year of life the right eye turned out increasingly and the right upper lid drooped. At the age of 11 months the child was taken to an ophthalmologist who operated on the outer muscle of the right eye, presumably doing a recession. The father had noticed changes in the size of the pupil in the past five or six months. No family history of ocular anomalies could be elicited from the parents. The boy has been seen frequently throughout the past year and one half, for the last time on February 2, 1962. The observations made are not necessarily reported in chronologic order but rep resent a composite picture. The child appeared well and normal in every respect, though possibly somewhat small for his age. He was quite hyperkinetic and difficult to ex amine. The right eye showed a complete flabby ptosis. When the lid was lifted the globe was seen to be deviated downward and outward. The pupil was dilated and did not respond to light either directly or consensually. There was virtually no adduction or elevation of the eye and little depression or ab duction. The globe itself, media and fundus, showed no abnormality. The left eye was normal in every respect and its vision was recorded to be 6/9 with single illiterate Es. If one watched the boy one noted that there would suddenly be a few twitches in the upper lid and then the lid would elevate with a single smooth * This patient was kindly referred to us in con sultation by Dr. Foster of Cedar Rapids, Iowa.
532
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN
V .#|èp#;'X
© -...Ar
î:
"
Fig. 1 (Burian and Van Allen). Photographs of cycle of spasm and relaxation. The pictures do not represent successive photographs of one cycle. A large number of photographs had to be taken in this unruly child from which these pictures were selected to represent with reasonable accuracy the sequence of the cycle. This explains why the left pupil is of different diameter in different pictures. movement so that the right lid fissure became es sentially equal in width to the left. There was a good lid fold. At the same time as the lid elevated the eye would move toward the middle and the pupil which was about six or seven mm. in diameter would constrict to about 1.5 mm. The eye would remain in this position for about 30 seconds, then the lid would slowly droop, the pupil dilate and the globe return to its deviated position. After one minute or so the spastic cycle would set in again (fig. 1). Refraction in atropine cycloplegia revealed: O.D., +2.0D. sph.3+0.5D. cyl. ax, 80°; O.S., +1.0D. sph. C +1.0D. cyl. ax. 100°. The vision of the right eye was 6/30 when the eye was in the relaxed phase and 6/12 when the eye was in the spastic phase, as determined with single illiterate Es. The vision of the left eye was 6/9. Intended movements of the eyes did not provoke one or the other phase of the cycle, but levoversion did tend to prolong the spastic phase and dextroversion the paralytic phase. Intent of fixation with the right eye appeared to shorten the period of transition from the paralytic to spastic phase and to
maintain the latter. It did not prevent the reap pearance of the paralytic phase. However, it was difficult to know whether the child was really at tempting to maintain fixation or whether he let his attention wander. Also, it appeared that when the boy made a levoversion movement during the spas tic phase the right eye was more adducted than when he made a levoversion movement during the paralytic phase (fig. 2). Drugs instilled into the cul-de-sac of the con junctiva had the expected effect. Atropine and its derivatives dilated the right pupil and interrupted the pupillary cycle. Pilocarpine produced miosis and also interrupted the pupillary cycle. Cocaine caused mydriasis but left the pupillary cycle unaffected, ex cept that the pupil appeared somewhat larger in the mydriatic phase and slightly less contracted in the miotic phase. The mother stated that the cyclic phenomenon was going on during sleep and the child was ob served by one of us (M. W. Van A.) during in duced sleep in the darkened EEG room. Infrequent twitching of the right upper lid was noted. How ever, one of our resident physicians (Dr. Roger S.
CYCLIC OCULOMOTOR PARALYSIS Kirkegaard) observed the child during sleep on the ward and found that when the lids were raised gently so as not to disturb the sleep the eyes were straight. The right pupil was two or three mm. in size and did not vary over a 15-minute period of observation. Slightly painful stimulation applied to an area around the eye, just enough to cause a little movement and a slightly lighter stage of sleep, resulted in marked dilatation of the right pupil lasting five to 10 sec, then returning to the constricted stage of two or three mm. The left pupil remained smaller than the right at all times, but also responded to the painful stimulus by di lating slightly. In the waking state the same ob server noted that the spastic phase of the pupil lasted 20 sec, the mydriatic phase 35 sec. In general anesthesia the following observations were made. In a light stage of anesthesia all cyclic movements stopped. The right eye was turned out and up, its pupil large (about 4.5 mm.), the left eye was turned down, its pupil small (about two mm). All cyclic movements stopped with this stage of light sleep under anesthesia. During the second and mid third stage the condition remained essen tially the same except that the right eye was turned up to a lesser degree. Both pupils were fixed. Neurologic examination of the child (M. W. Van A.) showed no deficits of the cranial nerves other than those of the third nerve, nor were there any other neurologic signs or defects. Two EEGs were obtained from this child. The first (July 15, 1960) was reported by Dr. John R. Knott: Record run—awake, no drowsiness, no sleep (0.75 gr. Seconal), no hyperventilation. Patient was restless, at best; much artefact was present. 1. Some 8.5 to 9.0 per second occipital alpha, bilaterally. 2. Dominant 7.0 to 7.5 per second theta, bi laterally. 3. No significant slow or fast. 4. Bilateral beta following Seconal but no drow siness or sleep activity. Impression* Within normal limits for age. The second EEG (November 5, 1961) was re ported by Dr. E. Niedermeyer as follows: Record Run—awake, hyperventilation, photic stimulation, drowsy and asleep (0.75 gr. Seconal). 1. Posterior medium voltage 8.0 per second alpha rhythm, slightly better developed at right. Normal response to eye opening. 2. Some diffuse medium voltage 1.5-3.0 and 4.07.0 per second activity, no significant fast activity. 3. No obvious changes during periods of "spas tic" or "paretic" function of the right oculomotor nerve. 4. With hyperventilation, diffuse build-up of high voltage 3.0 to 4.0 per second activity with rare interspersed small sharp potentials. 5. No response to photic stimulation. 6. While drowsy, a few brief bursts of general ized irregular high voltage 3.0 to 4.0 per second waves with intermixed spikes, slightly more de-
533
Fig. 2 (Burian and Van Allen), (a) Appearance of eyes in relaxed phase, (b) Attempted adduction in relaxed phase, (c) Attempted adduction in spas tic phase. veloped over right hemisphere. 7, Asleep, one brief burst of 6.0 to 7.0 per sec ond positive spikes over the posterior parts, other wise normal sleep. 8. After arousal from sleep, asymmetries in the temporal leads with pronounced medium voltage 1.0 to 4.0 per second activity at right temporal. Impression: Abnormal with rare bursts of gen eralized slow and spiky activity (while drowsy), one instance of six per second positive spikes (asleep) and minor asymmetries after arousal from sleep. This record suggests a deep-lying brain dis turbance ( ? brainstem level, ? rhinencephalon) of unknown etiology. In order to evaluate their therapeutic effective ness and at the same time to attempt to elucidate the etiology of this condition the child was placed on various drugs. He was placed on 15 mg. of phénobarbital (t.i.d.) on July 15, 1960. This had no effect, the boy was no more relaxed than with out the drug and found it no easier to go to sleep. On August 10, 1960, the dose was doubled, again with out effect. Phénobarbital was discontinued and in stead Dilantin was prescribed, giving at first 0.75 gr., b.i.d., later t.i.d. There was possibly a slight
534
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN
slowing of the cycle but not enough to warrant con tinuation of the drug. On September 8, 1960, the drug was discontinued and the boy was placed on Librium (Chlordiazepoxide hydrochloride, five mg. t.i.d.). He tolerated the medicine well but, again, there was no effect on the cycle. The dose was in creased to 25 mg. daily but, again, without any ap preciable effect on the eye. Librium was therefore discontinued and the patient placed again on Dilantin (0.75 gr. t.i.d.) Although the impression was that the cycle was again slowed by the drug, actual measurement did not support this observation and the drug was discontinued on January 10, 1961.
In summary, then, this is a rather typical case of cyclic oculomotor paralysis. The be havior of the pupil, of the levator muscle of the upper lid and of the medial rectus mus cle conform to the descriptions in the litera ture, as do the effect of intended eye move ments and of miotic and mydriatic drugs on the cyclic phenomena. Phénobarbital, Dilantin and Librium were essentially without effect. One observation which might be worth pointing out is the difficulty one had putting the boy to sleep. The mother stated that he did not like to go to sleep and that it took one hour to put the boy to sleep when he had his eye operation. While we found no such difficulties, it took a surprisingly large amount of anesthetic gas to put him under and he seemed quite unaffected by 0.75 gr. of Seconal when the first EEG was at tempted. It is of interest to note that two observers reported that their patients were very easily aroused from sleep (Uhthoff,9 Löwenstein and Givner 3 ). COMMENT
Cyclic oculomotor paralysis is not only rarely observed, it is also unique in that it has no known parallel among ophthalmic and neurologic manifestations of disease. This adds to the difficulties encountered by all attempts at a pathophysiologic explana tion of the striking condition. Clearly, there are two phenomena which demand an explanation. One is the localiza tion of the lesion causing the oculomotor pa ralysis, the other is the mechanism which produces the spontaneous rhythmic contrac
tion of some of the paralyzed muscles. Both have received varying interpretations. With the exception of Bielschowsky12 who saw 10, or one fourth, of all reported cases, and Hicks and Hosford 11 who saw two, all other observers have seen only one case. Al though they are basically similar, the cases differ in detail and different observers were more impressed by certain characteristics of the condition than by others and have, ac cordingly, so geared their explanation of the whole phenomenon. Fuchs 21 thought the lesion to be nuclear and spoke of the possibility that rhythmic variations in the blood supply might be re sponsible for the rhythmic increase and de crease in the innervation of the iris sphinc ter and lid levator muscles. Axenfeld and Schürenberg17 disagreed with Fuchs. 21 Because of the total paralysis, involving all branches of the oculomotor nerve, and particularly because of the uni lateral spasm of accommodation, they felt that the lesion had to be peripheral to the nucleus. They envisaged that somewhere pressure was being exerted on the nerve and that this pressure relaxed temporarily, ow ing to special vascular conditions, making way for a flow of innervation, and indeed for an excessive flow of innervation. These two authors also considered, in addition to this mechanism, the possibility that the effect of adduction and abduction of the affected eye on the spastic and relaxed phases, re spectively, resulted from aberrant regenera tion of nerve fibers. Salus13 attempted to explain the whole phenomenon on this basis but later revised his opinion,22 partly under the influence of criticism from Bielschowsky.12 The latter, who had devoted a good deal of attention to co-movements of the lid, contended that what appeared to be a pseudo-Graefe phe nomenon was in fact not a true pseudoGraefe phenomenon. In the former the re sponse is said to be much quicker than in the cases of cyclic oculomotor paralysis. Bielschowsky12 explained the effect of in-
CYCLIC OCULOMOTOR PARALYSIS
tended or actual movements of adduction and abduction on the two phases of the cyclic phenomenon by a presumed influence on the blood supply of the nuclei. He theorized that intended adduction increased the blood sup ply to the third-nerve nucleus, maintaining stimulation, whereas intended abduction with parallel increase in blood supply to the sixthnerve nucleus and decrease in blood supply to the third-nerve nucleus maintained the paralytic phase. It is understandable that early observers in whose patients only the pupil was impli cated in the cyclic process (Aurand and Breuil,4 Fromaget 5 ) concluded that the phe nomenon was akin to pathologic hippus of the pupil. However, Franke, 7 in 1909, al ready pointed out the difference between the two phenomena. Hippus is never congenital ; the nature of the rhythm in hippus is dif ferent and the change in pupillary size is at the most two to three mm. ; intended or ac tual eye movements have no influence on hippus; in hippus there is no unilateral spasm of accommodation. The most reasonable explanation of the clinical characteristics of cyclic oculomotor paralysis appears to be the one proposed by Bielschowsky12 and Behr.23 Briefly stated the hypothesis is as follows: Whatever pathologic process is responsi ble for the condition causes a destruction of part of the ganglion cells of the oculomotor nucleus. Other parts of the nucleus remain intact; always those supplying the sphincter muscle of the iris and the ciliary muscle, frequently those supplying the levator mus cle of the upper lid, and occasionally those supplying the medial rectus muscle. How ever, supranuclear structures adjacent to the oculomotor nucleus are also involved, as evi denced by the fact that the extraocular mus cles cannot be innervated voluntarily and that the pupil does not respond to physio logic stimuli. But the intactness of the nu clear structures is shown by the presence of a positive Bell's phenomenon and a positive orbicularis phenomenon in some cases and
535
by the responsiveness of the effector or gans to the abnormal rhythmic stimuli in all cases. Nevertheless, the supranuclear lesion cannot abolish completely all supranuclear stimuli. At least in those cases in which in tended movements of the eyes influence the cycle of spasm and relaxation, some impulses from cortical regions must come through. This assumption must be made, unless one accepts Bielschowsky's12 theory of variable local vasomotor effects on the nuclei. Bielschowsky's12 interpretation is unlikely in view of the observations that changes in respiration and in the rate of heartbeat up to 150 per minute have no effect on the cy clic phenomena (Aurand and Breuil,4 Groethuysen 16 ). It must be admitted that the origin of the rhythmic impulses to contrac tion is even less easily explained than the localization of the lesion producing the oc ulomotor paralysis. We favor the hypothesis that these rhythmic impulses have their origin in some automatic center in the diencephelon (fig. 3). It is conceivable that the supranu clear lesion has removed an inhibitory ac tivity which permits the remaining intact ganglion cells to the oculomotor nucleus to respond to these rhythmic impulses which are normally integrated into the function of that nucleus. If our view is correct, and we see no other obvious alternative, cyclic oculomotor pa ralysis is an unusual experiment of nature which reveals what is evident from no other source: a basic rhythmic activity of the vegetative centers. In this lies its contribu tion to physiology. SUMMARY
A typical case of right cyclic oculomotor paralysis in a three-year-old boy is re ported. We believe that the best explanation of the phenomenon was given by Bielschow sky and Behr, according to whom the con dition is due to a partial destruction of the oculomotor nucleus with involvement of the supranuclear fibers for pupillary light reac-
536
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN Fig. 3 (Burian and Van Allen). Diagram illus trating our concept of the possible nature of the lesion in cyclic oculomotor paralysis. Scattered in tranuclear destruction is suspected, with many neurons remaining functional. Most supranuclear (S.I.) and intemuclear (crossing fibers C.F.) in fluences are interrupted. The pathway (L.R.) of the light reflex of the pupil is blocked. Diencephalic influences (D.I.) retain access to the otherwise largely isolated unilateral nuclear mass. A hypothetical diencephalic rhythm impinges the functioning parasympathetic neurons of the nu cleus. Because other influences are largely elimi nated this rhythm becomes manifest in the cyclic pupillary and ciliary changes. Internuncials (I) carry this uninhibited neural discharge to the other neurons of the Illrd nerve nucleus, resulting in contraction of levator and medial rectus. A simul taneous nonreciprocal contraction may also take place in superior rectus, inferior rectus and infe rior oblique but eye position would be expected to change little in respect to this because of opposing action of these muscles.
tion and some corticonuclear fibers. We ex plain the automatism as resulting from a hy pothetical diencephalic rhythm impinging
upon the functioning parasympathetic neu rons of the nucleus. University Hospitals.
REFERENCES
1. Walsh, F. B.: Clinical Neuroophthalmology. Baltimore, Williams & Wilkins, 1957, ed. 2, pp. 168-169. 2. Bonnet, P. : Le phénomène cyclique du moteur oculaire commun. Syndrome probablement congénital, caractérisé par une paralysie totale du moteur oculaire commun, sans cesse et rythmiquement interrompue par la vive contraction de certain muscles paralysés. J. Méd. de Lyon, 22:209-220, 1941. 3. Löwenstein, O., and Givner, T.: Cyclic oculomotor paralysis (spasmus mobilis oculomotorius). Arch. Ophth., 28:821-833, 1942. 4. Aurand, L., and Breuil, P.: Contribution à l'étude de l'hippus pathologique. Un cas d'hippus rythmic monolatéral compliquant une paralysie dissociée de la III e paire. Arch, ophthal., 26:74-28, 1906. 5. Fromaget, C.: L'athétose pupillaire ou hippus. Arch, ophtal., 26:230-233, 1906. 6. Levinsohn, G.: Angeborene Okulomotoriuslähmung mit kontinuierlichem Pupillenspiel. Ztschr. Augenh., 17:341-347, 1907. 7. Franke, E.: Angeborene zyklische Okulomotoriuserkrankung und Hippus der Regenbogenhaut. Klin. Monatsbl. Augenh., 58(11) :582-592, 1909. 8. Paterson, J. V. : A case of congenital partial palsy of the third nerve with cyclical contraction and dilatation of the pupil. Ophth. Rev., 20:129-131, 1910. 9. Uhthoff, W. : Ueber einen Fall von periodischen und kontinuierlichen Schwankungen im Durchmes ser der Pupille bei angeborener oder wenigstens frühzeitig erworbener linksseitiger Okulomotoriusläh mung bei einem neunjährigen sonst gesunden Mädchen. Klin. Monatsbl. Augenh., 54(11) :344-346, 1913. 10. Stein, R. : Okulomotoriuslähmung mit zyklischer Innervation der inneren Augenmuskeln. Med. Klinik., 37(1) :350-352, 1931. 11. Hicks, A. M., and Hosford, G. N.: Cyclic paralysis of the oculomotor nerve. Arch. Ophth., 17: 213-222, 1937. 12. Bielschowsky, A.: (a) Ein Beitrag zur Kenntniss der Pupillenphänomene. Klin. Monatsbl. Augenh., 41:308-327, 1903. (b) Ueber die Oculomotoriuslähmung mit cyclischem Wechsel von Krampf und Erschlaffungszuständen am gelähmten Auge. Arch. f. Ophth., 121:659-685, 1929. (c) Die Lähmungen der Augenmuskeln. Graefe-Saemisch, Handbuch Augenh., Berlin, Springer, 1932, Chapter XI, Nachtrag I, pp. 216-220; 263-2171. 13. Salus, R. : Okulomotoriuslähmung mit abnormer zyklischer Innervation der inneren Äste. Kliti. Monatsbl. Augenh., 50(11) : 66-80, 1912. 14. Krämer, R.: Zwei Fälle eines Pupillenphaenomens. Presented on May 20, 1912. Ophth. Ges. Wien, reported in Ztschr. Augenh., 29:76-78, 1913. 15. Selinger, E.: Cyclic or rhythmic oculomotor paralysis. Arch. Ophth., 4:32-36, 1930.
CYCLIC OCULOMOTOR PARALYSIS
537
16. Groethuysen, G.: Ein Fall von zyklischer Okulomotoriuslähmung. Arch. f. Augenh., 76:265-268, 1914. 17. Axenfeld, Th., and Schürenberg, E.: Beiträge zur Kenntniss der angeborenen Beweglichkeitsdefekte der Augen. I. Angeborene cyclische Oculomotoriuserkrankung. Einseitiger Accommodationskrampf. Klin. Monatsbl. Augenh., 39(1) :64-73, 1901. 18. Kubik, J.: Ueber kongenitale Okulomotoriuslähmung mit erworbener zyklischer Innervation des inneren Okulomotorisusastes und des Levator palp. sup. Klin. Monatsbl. Augenh., 73 ( I I ) : 131-135, 1924. 19. Mak van Waay, A. W. H.: Ein Fall von zyklischer Okulomotoriuslähmung. Klin. Monatsbl. Augenh., 89(11) :36-45, 1932. 20. von Hippel, E.: Ueber angeborene zyklische Okulomotoriuserkrankung mit einseitigem Akkommodationskrampf (Axenfeld und Schürenberg). Klin. Monatsbl. Augenh., 52(1) :99-lll, 1914. 21. Fuchs, E.: Association von Lidbewegungen mit seitlichen Bewegungen der Augen. Beitr. Augenh., 2:12,1893. 22. Salus, R.: Zur Frage der Mitbewegungen der Pupille. Klin. Monatsbl. Augenh., 71(11) :289-305, 1923 (Part 2: Die angeborene zyklische Okulomotoriuserkrankung, p. 294-300). 23. Behr, G: Die Lehre von den Pupillenbewegungen. Graefe-Saemisch's Handb. Augenh., Berlin, Springer, 1924, ed. 3, v. 2. ADDITIONAL LITERATURE*
Drucker, A. P.: Cyclic rhythmic oculomotor paralysis: Case report. EETN Monthly, 28:274-276, 1949. Greeves, R. A.: Case of congenital oculomotor paralysis with synchronous contraction of muscles sup plied by the third cranial nerve. Proc. Royal Soc. Med., Section on Ophth., 6:23-26 (Pt. I l l ) 1912-1913. Herbert, H.: Oculomotor paralysis with rhythmic spasm. Ibid., pp. 96-99. Meissner: In discussion of Krämer." Ztschr. Augenh., 29:78, 1913. Mosso, G.: Midriasi alternante. Spasmi clonici-tonici oculo-palpebraile. Paralisi congenita unilaterale dell' oculomotorio comune. Ann. Ottal., 42:231-258, 1913. Petrovic, A., and Tschemolossow, A.: Zur Frage der rhythmischen Angiospasmen in Gebiete der Augenkerne. Klin. Monatsbl. Augenh., 86:491-496, 1931. Rampoldi, R.: (a) Singolarissimo caso di squilibrio motorio oculo-palpebrale. Ann. Ottal., 13:463-469, 1884. (b) Un nuovo caso di congenito squilibrio motorio oculo-palpebrale. Ann. Ottal., 15:54-56, 1886. Zamorini, V.: Un caso di paralisi del l'oculomotorio cummune. Atti Acad. di sci. med. e nat, Ferrara, July, 1913, reviewed in Jahresb. Ophth., 44:252, 1913. * These papers are added to give a complete and accurate bibliography of cyclic oculomotor paralysis for the convenience of interested readers. L E N S O P A C I T I E S PRODUCED BY CATARACTOGENIC A G E N T S * WITH
SPECIAL REFERENCE TO TRIPARANOL CATARACT JOHN
G. B E L L O W S ,
M.D.
Chicago, Illinois Recent warnings to physicians have stated that Mer-29, or triparanol, employed in the treatment of hypercholesterolemia, may pro duce cataracts in man. Triparanol must now be added to the ever-growing list of cataractogenic agents which may produce lens opac ities in susceptible species and individuals. Others are dinitrophenol, naphthalene, thal lium, ergot, galactose, alloxan,* diphenylthiocarbazone,1 mimosine,2 and corticosteroids.3 ♦From the Department of Ophthalmology, Northwestern University School of Medicine, and Cook County Hospital. t The opacities produced by alloxan intoxication are caused by the resulting diabetes mellitus.
The effects of all these agents vary remark ably from species to species and among in dividuals within species. This report will de scribe particularly cataracts caused by Mer29 therapy and show that these opacities, resembling those produced by other cataractogenic agents, are quite distinctive. It will be shown also that not all cataracts or opaci ties discovered in patients receiving or hav ing received Mer-29 are caused by this drug. My object is to warn physicians that all new systemic drugs should be viewed sus piciously and that patients receiving a new drug for a prolonged interval should un dergo frequent and thorough eye examina-
529
CONCLUSION Poor visual acuity following surgery for congenital cataract may depend upon the simultaneous presence of congenital ambly opia. Nystagmus is a frequent associate of con genital amblyopia and its presence predicts a probable poor visual prognosis. Visual acuity as good as 6/15 can occa sionally be obtained even in the presence of nystagmus. University Hospitals.
REFERENCES
1. Bagley, C. H.: Congenital cataracts. Am. J. Ophth., 32:411, 1949. 2. Carbajal, U. M.: A safe approach in surgery of congenital cataracts. Am. J. Ophth., 52:361, 1961. 3. Chandler, P. A.: Surgery of the lens in infancy. Arch. Ophth., 45:125, 1951. 4. Cordes, F. C : Surgery of congenital cataracts. Am. J. Ophth., 31:1073, 1950. 5. : Evaluation of the surgery of congenital cataracts. Arch. Ophth., 46:132, 1951. 6. : Failure in congenital cataract surgery. Am. J. Ophth., 43:1, 1957. 7. : Surgery in congenital cataracts. In Haik: Symposium on Diseases and Surgery of the Lens. St. Louis, Mosby, 1957, 8. : Linear extraction in congenital cataract surgery. Am. J. Ophth., 52:355, 1961. 9. Costenbader, F. D., and Albert, D. G. : Conservatism in the management of congenital cataract. AMA Arch. Ophth., 58:426, 1957. 10. Falls, H. F.: Developmental cataracts: Results of surgical treatment of 131 cases. Arch. Ophth., 29:210, 1943. 11. Gregg, N. M.: Congenital cataract following German measles in mother. Tr. Ophth. Soc. Australia, 3:35, 1942. 12. Jaffe, N. S., and Light, D. S.: Surgery of developmental cataract. AMA Arch. Ophth., 59:407. 1958. 13. Jones, I. S.: Needling of congenital cataracts. Am. J. Ophth., 52:347, 1961. 14. Kirby, D.: In Berens, C : The Eye and Its Diseases. Philadelphia Saunders, 1936. 15. Newton, F. H.: Congenital cataracts. Am. J. Ophth., 52:368, 1961. 16. Owens, W. C, and Hughes, W. F., Jr.: Results of surgical treatment of congenital cataract. Arch. Ophth., 39:339, 1948. 17. Wilson, W. A.: Congenital cataracts. AMA Arch. Ophth., 67:163, 1962. CYCLIC O C U L O M O T O R HERMANN
M.
B U R I A N , M.D.,
PARALYSIS*
AND M A U R I C E W.
V A N ALLEN,
M.D.
Iowa City, Iowa Among the rarest and most interesting forms of the paralyses of the third nerve is that which goes under the name of cyclic oculomotor paralysis, t In this condition some of the extraocular muscles over which * From the Neurosensory Center (Publication No. 9) and from the Departments of Ophthalmol ogy and Neurology, College of Medicine, State University of Iowa. The Neurosensory Center is supported by Program Project Grant B3354 of the National Institute of Neurolgical Diseases and Blindness, Bethesda, Maryland. Presented at the 98th annual meeting of the American Ophthalmo-
the patient has lost all voluntary control con tract spastically at more or less regular in tervals. The sphincter of the iris which is essentially nonresponsive to all physiologic stimuli, together with the paralyzed ciliary muscle, contracts synchronously with the ex traocular muscles. logical Society, Hot Springs, Virginia, May, 1962. t Walsh who has such a vast experience in the field of neuro-ophthalmology states that he has ob served only one example in a Negro boy shown at the New York Academy of Medicine.1
530
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN
We all know this condition from text books but few of us have actually seen it. The rarity of the condition and its pathophysiologic implications warrant the report ing of a case which we have had the oppor tunity to study. Before presenting this report it might be helpful to summarize some of the charac teristics of the cyclic oculomotor paralysis, as culled from the literature. Onset. In well over one half of the cases the condition was congenital or arose in the first six months of life. In four cases it could be reliably established that the oculo motor paralysis occurred many years prior to the onset of the cyclic phenomenon. There was no family history of either oculomotor paralysis or of the cyclic phenomenon with the exception of one case (Bonnet 2 ), where both mother and son were afflicted. No se vere illness preceded or coincided with the onset of the oculomotor paralysis. Degree of oculomotor involvement. In most of the reported cases the paralysis of the third nerve was complete, but in a few instances it was only partial, so far as the extraocular muscles were concerned. The pa tients could not raise the lid or adduct, ele vate or depress the globe. In the patients in whom the paralysis was not total certain of these movements could be performed to a degree. Pupillary responses to physiologic stimuli. The pupil of the affected eye did not re spond to light either directly or consensually, nor was there any response to convergence impulses or to sensory stimulation. Only Löwenstein and Givner3 found minimal pu pillary reactions in their patient by pupillography. This response was tonohaptic in nature. Structures involved in the cyclic phenom enon. The sphincter of the iris and most likely also the ciliary muscle were involved in every case. In a number of them (Aurand and Breuil,4 Fromaget,5 Levinsohn,6 Franke, 7 Paterson,8 Uhthoff,9 Stein,10 Hicks and Hosford, case l 11 ) these two muscles were the
only ones affected. Next in frequency was the levator muscle of the upper lid, and oc casionally the medial rectus muscle took part in the cycles of spasm and relaxation. Character and time course of the cyclic phenomena. In the phase of relaxation the upper lid hangs flabbily over the globe which is deviated outward and downward. The pu pil is dilated, accommodation is relaxed. This phase lasts for one to three minutes. In the full-blown cases one notes toward the end of this period twitching movements of the upper lid which then suddenly and smoothly rises to give the lid fissure its nor mal width. At the same time the mydriatic pupil constricts to a diameter of one to three mm., the eyeball moves to the midline and there is a spasm of accommodation. This is the spastic phase which may last from 30 to 100 seconds, depending on the case and the circumstances. Then there are again a few twitching movements of the upper lid, the eye suddenly turns out, the pupil dilates and the lid returns to its ptotic position. The cy cles of spasm and of relaxation repeat them selves with great regularity. As has been stated, in some cases only the pupil and the ciliary muscle are involved in the spastic cycle. It has also been noted in one or two instances that the phase of relax ation may last considerably longer on some days than on others. Effect of impulses to perform eye move ments on the cyclic phenomena. Eye move ments—or volitional impulses to perform an eye movement where such a movement is impossible owing to the paralysis—do not of themselves cause the appearance of either the spastic or the relaxed phase. But it has been established that certain intended eye move ments favor one or the other phase, prolong ing it at times indefinitely, or shortening the contrasting phase. Thus, adduction, or intended adduction, as well as convergence and fixation with the affected eye, favor the spastic phase, whereas abduction favors the phase of relaxation. Bielschowsky,12 Salus13 and others, have
CYCLIC OCULOMOTOR PARALYSIS
noted that depression in the spastic phase results in a pseudo-Graefelike phenomenon. In the phase of relaxation no such occur rence is observed when depression of the eyes is attempted. Where it was looked for Bell's phenome non was found to be present, although the patients were unable to elevate voluntarily the affected eye. In two instances (Levinsohn,e Krämer 14 ), the Westphal-Piltz reac tion (orbicularis phenomenon of the pupil) was positive. Influence of drugs on the pupillary cycle. Instillations of atropine caused maximal di latation of the pupil of the affected eye and abolished the pupillary cycle. Selinger15 re ported that his patient complained of rhyth mic pain in the eye with the use of pilo carpine, coinciding with the spastic phase, evidenced by contractions of the levator of the upper lid, although the pupillary cycle it self was abolished. Groethuysen10 mentioned similar pain with the use of eserine. He found that instillation of this drug, while producing a miosis of 1.8 to 2.5 mm, did not prevent the pupil from contracting fur ther during the spastic phase. Cocaine did not stop the cycle but caused dilatation of the pupil which did not constrict as much in the spastic phase as it did without the use of the drug. Adrenalin had no effect on either the width of the pupil or the pupillary cycle. Influence of sleep and anesthesia on the cyclic phenomena. Axenfeld and Schiirenberg" noted in their patient that during sleep the spastic phase occurred every two to five minutes, whereas it occurred in the wak ing state every one to three minutes. In three cases the phenomenon continued dur ing sleep (Bonnet,2 Kubik,18 Mak van Waay 19 ), but in Mak van Waay's case the spastic phase appeared to have been short ened and the relaxed phase considerably pro longed. In another case the eye was closed during sleep, but there were irregular twitches of the upper lid (v. Hippel 20 ), in two the cycle was abolished (Selinger,15 Uhtoff 9 ). It is of interest that it was noted
531
in two patients that the pupil could not be observed during sleep, because the patient slept extremely lightly (Uhthoff,9 Löwen stein and Givner 3 ). Uhthoff9 stated that the cycle was also abolished in general anesthesia. Influence of manipulations of the circu latory system on the cyclic phenomena. Nei ther slowing down or acceleration of respira tion (Aurand and Breuil 4 ) or an increase in pulse frequency to ISO (Aurand and Breuil,4 Groethuysen16) nor compression of the com mon carotid artery (v. Hippel 20 ) had any effect on the cyclic phenomena. CASE REPORT*
A white boy, born April 9, 1957, was seen by one of us (H. M. B.) on July 1960. He was the first child of the parents who stated that the preg nancy and delivery were normal. The boy's birthweight was nine pounds 11 ounces. The parents noted nothing wrong with the boy's eyes but the pediatrician mentioned that the right eye would not turn in. The right lid also appeared at first normal to the parents. During the first year of life the right eye turned out increasingly and the right upper lid drooped. At the age of 11 months the child was taken to an ophthalmologist who operated on the outer muscle of the right eye, presumably doing a recession. The father had noticed changes in the size of the pupil in the past five or six months. No family history of ocular anomalies could be elicited from the parents. The boy has been seen frequently throughout the past year and one half, for the last time on February 2, 1962. The observations made are not necessarily reported in chronologic order but rep resent a composite picture. The child appeared well and normal in every respect, though possibly somewhat small for his age. He was quite hyperkinetic and difficult to ex amine. The right eye showed a complete flabby ptosis. When the lid was lifted the globe was seen to be deviated downward and outward. The pupil was dilated and did not respond to light either directly or consensually. There was virtually no adduction or elevation of the eye and little depression or ab duction. The globe itself, media and fundus, showed no abnormality. The left eye was normal in every respect and its vision was recorded to be 6/9 with single illiterate Es. If one watched the boy one noted that there would suddenly be a few twitches in the upper lid and then the lid would elevate with a single smooth * This patient was kindly referred to us in con sultation by Dr. Foster of Cedar Rapids, Iowa.
532
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN
V .#|èp#;'X
© -...Ar
î:
"
Fig. 1 (Burian and Van Allen). Photographs of cycle of spasm and relaxation. The pictures do not represent successive photographs of one cycle. A large number of photographs had to be taken in this unruly child from which these pictures were selected to represent with reasonable accuracy the sequence of the cycle. This explains why the left pupil is of different diameter in different pictures. movement so that the right lid fissure became es sentially equal in width to the left. There was a good lid fold. At the same time as the lid elevated the eye would move toward the middle and the pupil which was about six or seven mm. in diameter would constrict to about 1.5 mm. The eye would remain in this position for about 30 seconds, then the lid would slowly droop, the pupil dilate and the globe return to its deviated position. After one minute or so the spastic cycle would set in again (fig. 1). Refraction in atropine cycloplegia revealed: O.D., +2.0D. sph.3+0.5D. cyl. ax, 80°; O.S., +1.0D. sph. C +1.0D. cyl. ax. 100°. The vision of the right eye was 6/30 when the eye was in the relaxed phase and 6/12 when the eye was in the spastic phase, as determined with single illiterate Es. The vision of the left eye was 6/9. Intended movements of the eyes did not provoke one or the other phase of the cycle, but levoversion did tend to prolong the spastic phase and dextroversion the paralytic phase. Intent of fixation with the right eye appeared to shorten the period of transition from the paralytic to spastic phase and to
maintain the latter. It did not prevent the reap pearance of the paralytic phase. However, it was difficult to know whether the child was really at tempting to maintain fixation or whether he let his attention wander. Also, it appeared that when the boy made a levoversion movement during the spas tic phase the right eye was more adducted than when he made a levoversion movement during the paralytic phase (fig. 2). Drugs instilled into the cul-de-sac of the con junctiva had the expected effect. Atropine and its derivatives dilated the right pupil and interrupted the pupillary cycle. Pilocarpine produced miosis and also interrupted the pupillary cycle. Cocaine caused mydriasis but left the pupillary cycle unaffected, ex cept that the pupil appeared somewhat larger in the mydriatic phase and slightly less contracted in the miotic phase. The mother stated that the cyclic phenomenon was going on during sleep and the child was ob served by one of us (M. W. Van A.) during in duced sleep in the darkened EEG room. Infrequent twitching of the right upper lid was noted. How ever, one of our resident physicians (Dr. Roger S.
CYCLIC OCULOMOTOR PARALYSIS Kirkegaard) observed the child during sleep on the ward and found that when the lids were raised gently so as not to disturb the sleep the eyes were straight. The right pupil was two or three mm. in size and did not vary over a 15-minute period of observation. Slightly painful stimulation applied to an area around the eye, just enough to cause a little movement and a slightly lighter stage of sleep, resulted in marked dilatation of the right pupil lasting five to 10 sec, then returning to the constricted stage of two or three mm. The left pupil remained smaller than the right at all times, but also responded to the painful stimulus by di lating slightly. In the waking state the same ob server noted that the spastic phase of the pupil lasted 20 sec, the mydriatic phase 35 sec. In general anesthesia the following observations were made. In a light stage of anesthesia all cyclic movements stopped. The right eye was turned out and up, its pupil large (about 4.5 mm.), the left eye was turned down, its pupil small (about two mm). All cyclic movements stopped with this stage of light sleep under anesthesia. During the second and mid third stage the condition remained essen tially the same except that the right eye was turned up to a lesser degree. Both pupils were fixed. Neurologic examination of the child (M. W. Van A.) showed no deficits of the cranial nerves other than those of the third nerve, nor were there any other neurologic signs or defects. Two EEGs were obtained from this child. The first (July 15, 1960) was reported by Dr. John R. Knott: Record run—awake, no drowsiness, no sleep (0.75 gr. Seconal), no hyperventilation. Patient was restless, at best; much artefact was present. 1. Some 8.5 to 9.0 per second occipital alpha, bilaterally. 2. Dominant 7.0 to 7.5 per second theta, bi laterally. 3. No significant slow or fast. 4. Bilateral beta following Seconal but no drow siness or sleep activity. Impression* Within normal limits for age. The second EEG (November 5, 1961) was re ported by Dr. E. Niedermeyer as follows: Record Run—awake, hyperventilation, photic stimulation, drowsy and asleep (0.75 gr. Seconal). 1. Posterior medium voltage 8.0 per second alpha rhythm, slightly better developed at right. Normal response to eye opening. 2. Some diffuse medium voltage 1.5-3.0 and 4.07.0 per second activity, no significant fast activity. 3. No obvious changes during periods of "spas tic" or "paretic" function of the right oculomotor nerve. 4. With hyperventilation, diffuse build-up of high voltage 3.0 to 4.0 per second activity with rare interspersed small sharp potentials. 5. No response to photic stimulation. 6. While drowsy, a few brief bursts of general ized irregular high voltage 3.0 to 4.0 per second waves with intermixed spikes, slightly more de-
533
Fig. 2 (Burian and Van Allen), (a) Appearance of eyes in relaxed phase, (b) Attempted adduction in relaxed phase, (c) Attempted adduction in spas tic phase. veloped over right hemisphere. 7, Asleep, one brief burst of 6.0 to 7.0 per sec ond positive spikes over the posterior parts, other wise normal sleep. 8. After arousal from sleep, asymmetries in the temporal leads with pronounced medium voltage 1.0 to 4.0 per second activity at right temporal. Impression: Abnormal with rare bursts of gen eralized slow and spiky activity (while drowsy), one instance of six per second positive spikes (asleep) and minor asymmetries after arousal from sleep. This record suggests a deep-lying brain dis turbance ( ? brainstem level, ? rhinencephalon) of unknown etiology. In order to evaluate their therapeutic effective ness and at the same time to attempt to elucidate the etiology of this condition the child was placed on various drugs. He was placed on 15 mg. of phénobarbital (t.i.d.) on July 15, 1960. This had no effect, the boy was no more relaxed than with out the drug and found it no easier to go to sleep. On August 10, 1960, the dose was doubled, again with out effect. Phénobarbital was discontinued and in stead Dilantin was prescribed, giving at first 0.75 gr., b.i.d., later t.i.d. There was possibly a slight
534
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN
slowing of the cycle but not enough to warrant con tinuation of the drug. On September 8, 1960, the drug was discontinued and the boy was placed on Librium (Chlordiazepoxide hydrochloride, five mg. t.i.d.). He tolerated the medicine well but, again, there was no effect on the cycle. The dose was in creased to 25 mg. daily but, again, without any ap preciable effect on the eye. Librium was therefore discontinued and the patient placed again on Dilantin (0.75 gr. t.i.d.) Although the impression was that the cycle was again slowed by the drug, actual measurement did not support this observation and the drug was discontinued on January 10, 1961.
In summary, then, this is a rather typical case of cyclic oculomotor paralysis. The be havior of the pupil, of the levator muscle of the upper lid and of the medial rectus mus cle conform to the descriptions in the litera ture, as do the effect of intended eye move ments and of miotic and mydriatic drugs on the cyclic phenomena. Phénobarbital, Dilantin and Librium were essentially without effect. One observation which might be worth pointing out is the difficulty one had putting the boy to sleep. The mother stated that he did not like to go to sleep and that it took one hour to put the boy to sleep when he had his eye operation. While we found no such difficulties, it took a surprisingly large amount of anesthetic gas to put him under and he seemed quite unaffected by 0.75 gr. of Seconal when the first EEG was at tempted. It is of interest to note that two observers reported that their patients were very easily aroused from sleep (Uhthoff,9 Löwenstein and Givner 3 ). COMMENT
Cyclic oculomotor paralysis is not only rarely observed, it is also unique in that it has no known parallel among ophthalmic and neurologic manifestations of disease. This adds to the difficulties encountered by all attempts at a pathophysiologic explana tion of the striking condition. Clearly, there are two phenomena which demand an explanation. One is the localiza tion of the lesion causing the oculomotor pa ralysis, the other is the mechanism which produces the spontaneous rhythmic contrac
tion of some of the paralyzed muscles. Both have received varying interpretations. With the exception of Bielschowsky12 who saw 10, or one fourth, of all reported cases, and Hicks and Hosford 11 who saw two, all other observers have seen only one case. Al though they are basically similar, the cases differ in detail and different observers were more impressed by certain characteristics of the condition than by others and have, ac cordingly, so geared their explanation of the whole phenomenon. Fuchs 21 thought the lesion to be nuclear and spoke of the possibility that rhythmic variations in the blood supply might be re sponsible for the rhythmic increase and de crease in the innervation of the iris sphinc ter and lid levator muscles. Axenfeld and Schürenberg17 disagreed with Fuchs. 21 Because of the total paralysis, involving all branches of the oculomotor nerve, and particularly because of the uni lateral spasm of accommodation, they felt that the lesion had to be peripheral to the nucleus. They envisaged that somewhere pressure was being exerted on the nerve and that this pressure relaxed temporarily, ow ing to special vascular conditions, making way for a flow of innervation, and indeed for an excessive flow of innervation. These two authors also considered, in addition to this mechanism, the possibility that the effect of adduction and abduction of the affected eye on the spastic and relaxed phases, re spectively, resulted from aberrant regenera tion of nerve fibers. Salus13 attempted to explain the whole phenomenon on this basis but later revised his opinion,22 partly under the influence of criticism from Bielschowsky.12 The latter, who had devoted a good deal of attention to co-movements of the lid, contended that what appeared to be a pseudo-Graefe phe nomenon was in fact not a true pseudoGraefe phenomenon. In the former the re sponse is said to be much quicker than in the cases of cyclic oculomotor paralysis. Bielschowsky12 explained the effect of in-
CYCLIC OCULOMOTOR PARALYSIS
tended or actual movements of adduction and abduction on the two phases of the cyclic phenomenon by a presumed influence on the blood supply of the nuclei. He theorized that intended adduction increased the blood sup ply to the third-nerve nucleus, maintaining stimulation, whereas intended abduction with parallel increase in blood supply to the sixthnerve nucleus and decrease in blood supply to the third-nerve nucleus maintained the paralytic phase. It is understandable that early observers in whose patients only the pupil was impli cated in the cyclic process (Aurand and Breuil,4 Fromaget 5 ) concluded that the phe nomenon was akin to pathologic hippus of the pupil. However, Franke, 7 in 1909, al ready pointed out the difference between the two phenomena. Hippus is never congenital ; the nature of the rhythm in hippus is dif ferent and the change in pupillary size is at the most two to three mm. ; intended or ac tual eye movements have no influence on hippus; in hippus there is no unilateral spasm of accommodation. The most reasonable explanation of the clinical characteristics of cyclic oculomotor paralysis appears to be the one proposed by Bielschowsky12 and Behr.23 Briefly stated the hypothesis is as follows: Whatever pathologic process is responsi ble for the condition causes a destruction of part of the ganglion cells of the oculomotor nucleus. Other parts of the nucleus remain intact; always those supplying the sphincter muscle of the iris and the ciliary muscle, frequently those supplying the levator mus cle of the upper lid, and occasionally those supplying the medial rectus muscle. How ever, supranuclear structures adjacent to the oculomotor nucleus are also involved, as evi denced by the fact that the extraocular mus cles cannot be innervated voluntarily and that the pupil does not respond to physio logic stimuli. But the intactness of the nu clear structures is shown by the presence of a positive Bell's phenomenon and a positive orbicularis phenomenon in some cases and
535
by the responsiveness of the effector or gans to the abnormal rhythmic stimuli in all cases. Nevertheless, the supranuclear lesion cannot abolish completely all supranuclear stimuli. At least in those cases in which in tended movements of the eyes influence the cycle of spasm and relaxation, some impulses from cortical regions must come through. This assumption must be made, unless one accepts Bielschowsky's12 theory of variable local vasomotor effects on the nuclei. Bielschowsky's12 interpretation is unlikely in view of the observations that changes in respiration and in the rate of heartbeat up to 150 per minute have no effect on the cy clic phenomena (Aurand and Breuil,4 Groethuysen 16 ). It must be admitted that the origin of the rhythmic impulses to contrac tion is even less easily explained than the localization of the lesion producing the oc ulomotor paralysis. We favor the hypothesis that these rhythmic impulses have their origin in some automatic center in the diencephelon (fig. 3). It is conceivable that the supranu clear lesion has removed an inhibitory ac tivity which permits the remaining intact ganglion cells to the oculomotor nucleus to respond to these rhythmic impulses which are normally integrated into the function of that nucleus. If our view is correct, and we see no other obvious alternative, cyclic oculomotor pa ralysis is an unusual experiment of nature which reveals what is evident from no other source: a basic rhythmic activity of the vegetative centers. In this lies its contribu tion to physiology. SUMMARY
A typical case of right cyclic oculomotor paralysis in a three-year-old boy is re ported. We believe that the best explanation of the phenomenon was given by Bielschow sky and Behr, according to whom the con dition is due to a partial destruction of the oculomotor nucleus with involvement of the supranuclear fibers for pupillary light reac-
536
HERMANN M. BURIAN AND MAURICE W. VAN ALLEN Fig. 3 (Burian and Van Allen). Diagram illus trating our concept of the possible nature of the lesion in cyclic oculomotor paralysis. Scattered in tranuclear destruction is suspected, with many neurons remaining functional. Most supranuclear (S.I.) and intemuclear (crossing fibers C.F.) in fluences are interrupted. The pathway (L.R.) of the light reflex of the pupil is blocked. Diencephalic influences (D.I.) retain access to the otherwise largely isolated unilateral nuclear mass. A hypothetical diencephalic rhythm impinges the functioning parasympathetic neurons of the nu cleus. Because other influences are largely elimi nated this rhythm becomes manifest in the cyclic pupillary and ciliary changes. Internuncials (I) carry this uninhibited neural discharge to the other neurons of the Illrd nerve nucleus, resulting in contraction of levator and medial rectus. A simul taneous nonreciprocal contraction may also take place in superior rectus, inferior rectus and infe rior oblique but eye position would be expected to change little in respect to this because of opposing action of these muscles.
tion and some corticonuclear fibers. We ex plain the automatism as resulting from a hy pothetical diencephalic rhythm impinging
upon the functioning parasympathetic neu rons of the nucleus. University Hospitals.
REFERENCES
1. Walsh, F. B.: Clinical Neuroophthalmology. Baltimore, Williams & Wilkins, 1957, ed. 2, pp. 168-169. 2. Bonnet, P. : Le phénomène cyclique du moteur oculaire commun. Syndrome probablement congénital, caractérisé par une paralysie totale du moteur oculaire commun, sans cesse et rythmiquement interrompue par la vive contraction de certain muscles paralysés. J. Méd. de Lyon, 22:209-220, 1941. 3. Löwenstein, O., and Givner, T.: Cyclic oculomotor paralysis (spasmus mobilis oculomotorius). Arch. Ophth., 28:821-833, 1942. 4. Aurand, L., and Breuil, P.: Contribution à l'étude de l'hippus pathologique. Un cas d'hippus rythmic monolatéral compliquant une paralysie dissociée de la III e paire. Arch, ophthal., 26:74-28, 1906. 5. Fromaget, C.: L'athétose pupillaire ou hippus. Arch, ophtal., 26:230-233, 1906. 6. Levinsohn, G.: Angeborene Okulomotoriuslähmung mit kontinuierlichem Pupillenspiel. Ztschr. Augenh., 17:341-347, 1907. 7. Franke, E.: Angeborene zyklische Okulomotoriuserkrankung und Hippus der Regenbogenhaut. Klin. Monatsbl. Augenh., 58(11) :582-592, 1909. 8. Paterson, J. V. : A case of congenital partial palsy of the third nerve with cyclical contraction and dilatation of the pupil. Ophth. Rev., 20:129-131, 1910. 9. Uhthoff, W. : Ueber einen Fall von periodischen und kontinuierlichen Schwankungen im Durchmes ser der Pupille bei angeborener oder wenigstens frühzeitig erworbener linksseitiger Okulomotoriusläh mung bei einem neunjährigen sonst gesunden Mädchen. Klin. Monatsbl. Augenh., 54(11) :344-346, 1913. 10. Stein, R. : Okulomotoriuslähmung mit zyklischer Innervation der inneren Augenmuskeln. Med. Klinik., 37(1) :350-352, 1931. 11. Hicks, A. M., and Hosford, G. N.: Cyclic paralysis of the oculomotor nerve. Arch. Ophth., 17: 213-222, 1937. 12. Bielschowsky, A.: (a) Ein Beitrag zur Kenntniss der Pupillenphänomene. Klin. Monatsbl. Augenh., 41:308-327, 1903. (b) Ueber die Oculomotoriuslähmung mit cyclischem Wechsel von Krampf und Erschlaffungszuständen am gelähmten Auge. Arch. f. Ophth., 121:659-685, 1929. (c) Die Lähmungen der Augenmuskeln. Graefe-Saemisch, Handbuch Augenh., Berlin, Springer, 1932, Chapter XI, Nachtrag I, pp. 216-220; 263-2171. 13. Salus, R. : Okulomotoriuslähmung mit abnormer zyklischer Innervation der inneren Äste. Kliti. Monatsbl. Augenh., 50(11) : 66-80, 1912. 14. Krämer, R.: Zwei Fälle eines Pupillenphaenomens. Presented on May 20, 1912. Ophth. Ges. Wien, reported in Ztschr. Augenh., 29:76-78, 1913. 15. Selinger, E.: Cyclic or rhythmic oculomotor paralysis. Arch. Ophth., 4:32-36, 1930.
CYCLIC OCULOMOTOR PARALYSIS
537
16. Groethuysen, G.: Ein Fall von zyklischer Okulomotoriuslähmung. Arch. f. Augenh., 76:265-268, 1914. 17. Axenfeld, Th., and Schürenberg, E.: Beiträge zur Kenntniss der angeborenen Beweglichkeitsdefekte der Augen. I. Angeborene cyclische Oculomotoriuserkrankung. Einseitiger Accommodationskrampf. Klin. Monatsbl. Augenh., 39(1) :64-73, 1901. 18. Kubik, J.: Ueber kongenitale Okulomotoriuslähmung mit erworbener zyklischer Innervation des inneren Okulomotorisusastes und des Levator palp. sup. Klin. Monatsbl. Augenh., 73 ( I I ) : 131-135, 1924. 19. Mak van Waay, A. W. H.: Ein Fall von zyklischer Okulomotoriuslähmung. Klin. Monatsbl. Augenh., 89(11) :36-45, 1932. 20. von Hippel, E.: Ueber angeborene zyklische Okulomotoriuserkrankung mit einseitigem Akkommodationskrampf (Axenfeld und Schürenberg). Klin. Monatsbl. Augenh., 52(1) :99-lll, 1914. 21. Fuchs, E.: Association von Lidbewegungen mit seitlichen Bewegungen der Augen. Beitr. Augenh., 2:12,1893. 22. Salus, R.: Zur Frage der Mitbewegungen der Pupille. Klin. Monatsbl. Augenh., 71(11) :289-305, 1923 (Part 2: Die angeborene zyklische Okulomotoriuserkrankung, p. 294-300). 23. Behr, G: Die Lehre von den Pupillenbewegungen. Graefe-Saemisch's Handb. Augenh., Berlin, Springer, 1924, ed. 3, v. 2. ADDITIONAL LITERATURE*
Drucker, A. P.: Cyclic rhythmic oculomotor paralysis: Case report. EETN Monthly, 28:274-276, 1949. Greeves, R. A.: Case of congenital oculomotor paralysis with synchronous contraction of muscles sup plied by the third cranial nerve. Proc. Royal Soc. Med., Section on Ophth., 6:23-26 (Pt. I l l ) 1912-1913. Herbert, H.: Oculomotor paralysis with rhythmic spasm. Ibid., pp. 96-99. Meissner: In discussion of Krämer." Ztschr. Augenh., 29:78, 1913. Mosso, G.: Midriasi alternante. Spasmi clonici-tonici oculo-palpebraile. Paralisi congenita unilaterale dell' oculomotorio comune. Ann. Ottal., 42:231-258, 1913. Petrovic, A., and Tschemolossow, A.: Zur Frage der rhythmischen Angiospasmen in Gebiete der Augenkerne. Klin. Monatsbl. Augenh., 86:491-496, 1931. Rampoldi, R.: (a) Singolarissimo caso di squilibrio motorio oculo-palpebrale. Ann. Ottal., 13:463-469, 1884. (b) Un nuovo caso di congenito squilibrio motorio oculo-palpebrale. Ann. Ottal., 15:54-56, 1886. Zamorini, V.: Un caso di paralisi del l'oculomotorio cummune. Atti Acad. di sci. med. e nat, Ferrara, July, 1913, reviewed in Jahresb. Ophth., 44:252, 1913. * These papers are added to give a complete and accurate bibliography of cyclic oculomotor paralysis for the convenience of interested readers. L E N S O P A C I T I E S PRODUCED BY CATARACTOGENIC A G E N T S * WITH
SPECIAL REFERENCE TO TRIPARANOL CATARACT JOHN
G. B E L L O W S ,
M.D.
Chicago, Illinois Recent warnings to physicians have stated that Mer-29, or triparanol, employed in the treatment of hypercholesterolemia, may pro duce cataracts in man. Triparanol must now be added to the ever-growing list of cataractogenic agents which may produce lens opac ities in susceptible species and individuals. Others are dinitrophenol, naphthalene, thal lium, ergot, galactose, alloxan,* diphenylthiocarbazone,1 mimosine,2 and corticosteroids.3 ♦From the Department of Ophthalmology, Northwestern University School of Medicine, and Cook County Hospital. t The opacities produced by alloxan intoxication are caused by the resulting diabetes mellitus.
The effects of all these agents vary remark ably from species to species and among in dividuals within species. This report will de scribe particularly cataracts caused by Mer29 therapy and show that these opacities, resembling those produced by other cataractogenic agents, are quite distinctive. It will be shown also that not all cataracts or opaci ties discovered in patients receiving or hav ing received Mer-29 are caused by this drug. My object is to warn physicians that all new systemic drugs should be viewed sus piciously and that patients receiving a new drug for a prolonged interval should un dergo frequent and thorough eye examina-