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Experimental Oculomotor Nerve Regeneration
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ELECTRIC CATARACT Case 3 is interesting in that the patient was unaware of any visual damage until 13 months after the accident. SUMMARY
Three typical cases of cataract following electric shock are reported. Cataract extrac tion afforded an opportunity to examine sec tions of one lens. It is probable that early changes, consisting of anterior subcapsular vacuolization, may be detected within a few hours following shock and that these obser vations may be of aid in determining the visual prognosis. 227 16th Street
(80202).
REFERENCES
1. Godtf redsen, E. : Cataracta electrica and electrocardiographic changes after electric shock. Acta ophth. 20:69, 1942. 2. Long, J. C. : A clinical and experimental study of electric cataract. Tr. Am. Ophth. Soc. 60:471, 1962; Am. J. Ophth. 56:108, 1963. 3. Ellett, E. C. : Cataract caused by a discharge of industrial electricity. Ophth. Record, 15:4, 1906. 4. Bichelonne : Cataracte unilatérale après elec trocution industrielle. Ann. ocul. 144:108, 1910. 5. Morax, V. : Lésions irido-ciliares et cristalliniennes consécutives à la décharge électrique des courants de haut voltage. Ann. ocul. 155 :336, 1918. 6. Gabriélidès, A. : Contribution a l'étude des cataractes électriques. Arch, ophthal. 52 :394, 1935. 7. Neblett, H. : Bilateral cataract from electric shock. South Med. & Surg. 106:12, 1944. 8. Long, J. C. : Silhouette photography of opa cities of the ocular media. Am. J. Ophth. 56:761, 1963.
EXPERIMENTAL OCULOMOTOR NERVE D O N A L D J.
LYLE,
REGENERATION
M.D.
Cincinnati, Ohio There are many aspects of interest in neuro-ophthalmology which are controver sial. T h e conditions I have in mind occur as the result of neural damage, frequently with the attempt at repair and the effort to re store function by direct or secondary com pensatory means. These conditions appear to me to be con troversial because the fundamental basic knowledge of their production is lacking. This frequently implies that anatomy, phys iology and the stages of degeneration and regeneration have not been thoroughly studied. T h e explanation of the condition, seen clinically, has been stated, frequently dog matically, by earlier authors without thor ough investigation and has been reported and copied by successive discussors and writers without, apparently, considering its plausibility. I n the mind of these authors the subject is not controversial but a wellestablished fact.
O L D CONCEPT
There is one explanation which I could not accept, and that is the specific aberrant mis direction of the regenerating oculomotor axons. It is generally stated, and accepted, that the various axons of this nerve, during regeneration, pursue a misdirected course from their cell nuclei to a muscle other than the one they originally and normally inner vated, resulting in an erroneous and per verted ocular movement, with neutralized verticle action, lid retraction and some evi dence of pupil constriction. It has been shown in lower forms of ani mals, and in the newborn in the stages of development, that there is an orderly prog ress of axons to their predestined termina tions made easy through loosely formed and adequately vascularized tissue. In contrast, however, in the adult, following degenera tion of the injured third nerve, there is ob struction to the progress of axons of the re generating nerve by densely formed glial or
1240/300
DONALD J. LYLE
scar tissue, which is inadequately vascularized. Evidence is lacking that anything but chance determines the direction of regener ating axons. They pursue the course of least resistance to their muscular destination and not in a specific misdirected pattern, as as sumed in the old concept. If there is a predestined termination for the branches of the oculomotor nerve in fetal development, why then does such bi zarre innervation occur clinically following damage? If there has not been complete damage to the structures of the nerve, there is a good chance that the old conduit can be used, and the reinnervation to the proper termination accomplished. If, however, the damage produces a block and the loss of proper channeling, chance, and not a specific aberrant course, which has been assumed, redirects the regenerating axons. Misdirec tion of axons may occur, but not in a regu lar and predictable manner. It is important to emphasize Cajal's clas sic experiments which showed that, after a nerve has been sectioned, there are more re generated fibers than were originally pres ent. Presumably, if this excessive innerva tion reaches its destination and is able to function, a stimulus would provide an ex cessive reaction in the distal neuromuscular elements of the damaged nerve. Restored function from reinnervation may therefore be in excess and mass re sponses may occur. I recall, some years ago, having seen and heard Fritz Kreisler, the violinist, from a front seat in the audience. He had just recovered from paralysis of his right facial nerve and, during his perfor mance, during certain movements, I recog nized that the half of his face was contract ed into an extensive spasm from his concen tration. This was an en masse reaction of the entire innervation of the damaged facial nerve which had regenerated. From the supranuclear side we find this en masse reaction in the retraction syn drome, where the eyes are retracted into the orbits by the simultaneous contraction of the
retractor (rectus) muscles, instigated usual ly by the effort of adduction or convergence. This might imply the release of inhibiting control which induces excessive reaction on the part of the extraocular muscles. This en masse reaction seems to me to be borne out by the fact that the vertical eye movements, although receiving stimulation, are neutralized and thus immobilized by the en masse nuclear stimulation. The lid eleva tion and adduction are unopposed. When the eye is directed temporally, the oculomo tor-supplied muscles are equally relaxed. We find that, when there is adduction by effort on the part of the medial rectus, the lid is elevated, and, when abducted, the lid is ptosed. Thus, all the muscles innervated by the oculomotor nerve are simultaneously stimulated or relaxed. Bender's and Fulton's research in this field confirms this deduction.1 EXPERIMENTAL INVESTIGATION
There is, to date, a rather surprising difference of opinion as to the location of the cell groups within the oculomotor nu cleus complex serving the various oculomo tor supplied ocular muscles. Experimental studies in animals in which a specific muscle has been removed and/or its nerve supply destroyed, followed by de generation to a certain portion of the oculo motor nucleus, have been described by sev eral authors. These authorities are not in accord as to the shape and distribution of the subnuclei or cell groups within the com plex from study of retrograde degeneration and reaction from nuclear stimulation. Bernheimer (1897), Bach (1899), Browwer (1918), Bender and Weinstein (1943) and Warwick (1953) and a number of others came to somewhat different conclu sions as to : 1. The shape of the oculomotor nucleus. 2. The disposition of its component subnuclei serving the various ocular muscles. 3. The disposition and number of crossed and bilateral innervations.
OCULOMOTOR NERVE REGENERATION
Animal experimentation poses various influences for consideration which might ac count for some of the diverse conclusions. They are : 1. Time of study after operation. Cells disappear after too long a time following damage and it is better to study the degener ating cell than no cell at all. 2. Nature of the lesion—severing, crush ing, inflammation, etc. 3. Distance of lesion from the nucleus. 4. Difference in species. 5. The age of the subject. Crosby states2 "Discrepancies in tech nique must await further facts for their res olution for it is evident that little is to be gained by conjecture in the present state of knowledge concerning the integration of the ocular musculature." Generally speaking, with damage to the nerve in the monkey (Macaca mullata), after 10 days the oculomotor nuclei are affected, showing chromatolysis or other ev idence of degeneration affecting about 40% of the entire ipsilateral nucleus and 10% of the contralateral nucleus in which the lower third is chiefly involved. This degenerative process continues until chromatolysis is at its maximal stage, about 30 days (some au thors say half this time). If there is to be recovery, regeneration appears to be insti tuted at this time in the intraorbital and intracranial nerve and the nucleus. More recent investigators reported crossed connections to the troclear and abducens nuclei and less crossings have been advocated to the oculomotor nuclear compo nents. Warwick 3 states that the elevators of both lids have a common medial pool (in the monkey, in the caudal portion of the central nucleus serving both levator muscles). He found that after one levator nerve was de stroyed only half of the nucleus was affect ed and contralateral chromatolytic changes were found. He also found changes in the contralateral area serving the superior rectus muscle and in no other contralateral areas.
1241/301
PRESENT EXPERIMENT
The right oculomotor nerve was severed intracranially in the middle fossa in eight monkeys without trauma to adjacent struc tures. The severed ends were separated by less than a mm. A complete third-nerve pa ralysis resulted, with dilated pupil, ptosis and extraocular paralysis, save for the sixth and fourth innervated muscles. In three weeks following operation, there developed the beginning of a teeter-totter of the upper lids which persisted for several weeks with very little change. When the monkey looked to the left, the right lid was raised (pseudo-Graefe sign) and the left lid lowered. When the monkey looked to the right the ptosis of the right lid reappeared and the palpebral space on the left side was widened. Looking from side to side the teet er-totter was seen (fig. 1). The pupil of the operated side remained fairly well dilated during this period. After six weeks, the teeter-totter phenomenon became less evi dent, possibly as regeneration progressed, sometimes to normal (four months except ing pupil size and reaction), subnormal (persistent) or, possibly, other aberrant types of function, which were demonstrated by the pseudo-Graefe phenomenon or Gower's sign (1879), or Fuchs' sign (1893), in which the upper lid is elevated, widening the palpebral space with efforts of adduc tion and inf raduction. With the effort to place the eye in any of the directions served by the muscles inner vated by the oculomotor nerve through en masse stimulation, there was in the affected eye upon attempted adduction : 1. Equally opposed vertical muscle stimu lation and, therefore, no, or very slight, ver tical movement. 2. Some adduction from unopposed medi al rectus muscle with relaxation of the later al rectus (abducens). 3. Elevation of the upper lid from unop posed stimulation of the levator muscle with widening of the palpebral space (pseudoGraefe sign).
1242/302
DONALD J. LYLE
4. Upon abduction, with abducens stimu lation, ptosis was re-established and all other oculomotor action suppressed. 5. T h e pupil may or may not contract on adduction and dilate on abduction. This phenomenon in part (that is, the lid
movement) is reversed by the opposite eye which, although its third nerve remains in tact, manifests the same type of levator muscle reaction, which confirms Warwick's conclusion of a common levator pool. This en masse stimulus appeared to be so
Fig. 1 (Lyle). Ocular findings in monkey after right oculomotor nerve was severed intracranially in the middle fossa without trauma to adjacent structures. (Upper left) Looking right. (Upper right) Look ing forward. (Lower left) Looking left. (Lower right) Looking far left.
OCULOMOTOR NERVE REGENERATION dominating that only with great difficulty were we able to have the monkey look to the right side with the functioning abducens (the lateral rectus muscle), which one would believe would actually be the position of preference or of rest. T h e monkey pre ferred to keep looking to the left with ptosis of the left lid, so much so that those ob servers who did not know which side was operated believed the left oculomotor was cut and not the right. All the monkeys be haved in this manner. Clinical studies of oculomotor degenera tion and regeneration are, for obvious rea sons, incomplete. These animal experiments present a more complete study in that they have been observed from the sectioning of the oculomotor nerve in the middle fossa to the autopsy examination of the oculomotor nuclei.
1243/303
tigation of regeneration of peripheral and other cranial nerves, in addition to clinical evidence reported here and elsewhere, to as sume this is an "en masse" reaction with "all or none" response, with loss of the specific predestined individual muscular in nervation from a nuclear cell group. This is evidenced consistently in the pres ent experiment, in the monkeys studied, in the reaction of the extraocular muscles served by the oculomotor nerve. T h e intra ocular muscles, the dilator of the pupil and ciliary, appear to respond in lesser degree to regeneration and stimulation. Finally, I should like to state that this study might be termed a concept and not an established fact. It requires further investi gation, especially in its application to hu mans. 411 Oak Street (19). REFERENCES
CONCLUSION
N o one, to my knowledge, has ever traced an aberrant axon from its specific cellular location in the oculomotor nucleus to its muscular innervation, proving the assump tion of its misdirected course. It appears to me more reasonable, and with supporting evidence from recent inves
OPHTHALMIC
1. Bender, M. B., and Fulton, J. F. : Functional recovery in ocular muscles of a chimpanzie after section of the oculomotor nerve. J. Neurophysol. 1:144,1938. 2. Crosby, E. C, Humphrey, T., and Lauer, E. W. : Correlative Anatomy of the Nervous System. New York, Macmillan, 1962, p. 242. 3. Warwick, R. : In the Oculomotor System. (Ed ited by Bender, M. B.) New York, Hoeber, 1964 p. 173-204.
MINIATURE
Those who are unacquainted with the anatomy of the eye can only acquire this knowledge perfectly by dissections, which should be repeated on the dead eyes of animals ; but particularly of the human subject. A few dissections will impress the mind with more complete ideas of the eye than a thousand written descriptions. A Treatise on 118 Principle
Diseases of the Eyes and Eyelids William Rowley, London, 1790
ELECTRIC CATARACT Case 3 is interesting in that the patient was unaware of any visual damage until 13 months after the accident. SUMMARY
Three typical cases of cataract following electric shock are reported. Cataract extrac tion afforded an opportunity to examine sec tions of one lens. It is probable that early changes, consisting of anterior subcapsular vacuolization, may be detected within a few hours following shock and that these obser vations may be of aid in determining the visual prognosis. 227 16th Street
(80202).
REFERENCES
1. Godtf redsen, E. : Cataracta electrica and electrocardiographic changes after electric shock. Acta ophth. 20:69, 1942. 2. Long, J. C. : A clinical and experimental study of electric cataract. Tr. Am. Ophth. Soc. 60:471, 1962; Am. J. Ophth. 56:108, 1963. 3. Ellett, E. C. : Cataract caused by a discharge of industrial electricity. Ophth. Record, 15:4, 1906. 4. Bichelonne : Cataracte unilatérale après elec trocution industrielle. Ann. ocul. 144:108, 1910. 5. Morax, V. : Lésions irido-ciliares et cristalliniennes consécutives à la décharge électrique des courants de haut voltage. Ann. ocul. 155 :336, 1918. 6. Gabriélidès, A. : Contribution a l'étude des cataractes électriques. Arch, ophthal. 52 :394, 1935. 7. Neblett, H. : Bilateral cataract from electric shock. South Med. & Surg. 106:12, 1944. 8. Long, J. C. : Silhouette photography of opa cities of the ocular media. Am. J. Ophth. 56:761, 1963.
EXPERIMENTAL OCULOMOTOR NERVE D O N A L D J.
LYLE,
REGENERATION
M.D.
Cincinnati, Ohio There are many aspects of interest in neuro-ophthalmology which are controver sial. T h e conditions I have in mind occur as the result of neural damage, frequently with the attempt at repair and the effort to re store function by direct or secondary com pensatory means. These conditions appear to me to be con troversial because the fundamental basic knowledge of their production is lacking. This frequently implies that anatomy, phys iology and the stages of degeneration and regeneration have not been thoroughly studied. T h e explanation of the condition, seen clinically, has been stated, frequently dog matically, by earlier authors without thor ough investigation and has been reported and copied by successive discussors and writers without, apparently, considering its plausibility. I n the mind of these authors the subject is not controversial but a wellestablished fact.
O L D CONCEPT
There is one explanation which I could not accept, and that is the specific aberrant mis direction of the regenerating oculomotor axons. It is generally stated, and accepted, that the various axons of this nerve, during regeneration, pursue a misdirected course from their cell nuclei to a muscle other than the one they originally and normally inner vated, resulting in an erroneous and per verted ocular movement, with neutralized verticle action, lid retraction and some evi dence of pupil constriction. It has been shown in lower forms of ani mals, and in the newborn in the stages of development, that there is an orderly prog ress of axons to their predestined termina tions made easy through loosely formed and adequately vascularized tissue. In contrast, however, in the adult, following degenera tion of the injured third nerve, there is ob struction to the progress of axons of the re generating nerve by densely formed glial or
1240/300
DONALD J. LYLE
scar tissue, which is inadequately vascularized. Evidence is lacking that anything but chance determines the direction of regener ating axons. They pursue the course of least resistance to their muscular destination and not in a specific misdirected pattern, as as sumed in the old concept. If there is a predestined termination for the branches of the oculomotor nerve in fetal development, why then does such bi zarre innervation occur clinically following damage? If there has not been complete damage to the structures of the nerve, there is a good chance that the old conduit can be used, and the reinnervation to the proper termination accomplished. If, however, the damage produces a block and the loss of proper channeling, chance, and not a specific aberrant course, which has been assumed, redirects the regenerating axons. Misdirec tion of axons may occur, but not in a regu lar and predictable manner. It is important to emphasize Cajal's clas sic experiments which showed that, after a nerve has been sectioned, there are more re generated fibers than were originally pres ent. Presumably, if this excessive innerva tion reaches its destination and is able to function, a stimulus would provide an ex cessive reaction in the distal neuromuscular elements of the damaged nerve. Restored function from reinnervation may therefore be in excess and mass re sponses may occur. I recall, some years ago, having seen and heard Fritz Kreisler, the violinist, from a front seat in the audience. He had just recovered from paralysis of his right facial nerve and, during his perfor mance, during certain movements, I recog nized that the half of his face was contract ed into an extensive spasm from his concen tration. This was an en masse reaction of the entire innervation of the damaged facial nerve which had regenerated. From the supranuclear side we find this en masse reaction in the retraction syn drome, where the eyes are retracted into the orbits by the simultaneous contraction of the
retractor (rectus) muscles, instigated usual ly by the effort of adduction or convergence. This might imply the release of inhibiting control which induces excessive reaction on the part of the extraocular muscles. This en masse reaction seems to me to be borne out by the fact that the vertical eye movements, although receiving stimulation, are neutralized and thus immobilized by the en masse nuclear stimulation. The lid eleva tion and adduction are unopposed. When the eye is directed temporally, the oculomo tor-supplied muscles are equally relaxed. We find that, when there is adduction by effort on the part of the medial rectus, the lid is elevated, and, when abducted, the lid is ptosed. Thus, all the muscles innervated by the oculomotor nerve are simultaneously stimulated or relaxed. Bender's and Fulton's research in this field confirms this deduction.1 EXPERIMENTAL INVESTIGATION
There is, to date, a rather surprising difference of opinion as to the location of the cell groups within the oculomotor nu cleus complex serving the various oculomo tor supplied ocular muscles. Experimental studies in animals in which a specific muscle has been removed and/or its nerve supply destroyed, followed by de generation to a certain portion of the oculo motor nucleus, have been described by sev eral authors. These authorities are not in accord as to the shape and distribution of the subnuclei or cell groups within the com plex from study of retrograde degeneration and reaction from nuclear stimulation. Bernheimer (1897), Bach (1899), Browwer (1918), Bender and Weinstein (1943) and Warwick (1953) and a number of others came to somewhat different conclu sions as to : 1. The shape of the oculomotor nucleus. 2. The disposition of its component subnuclei serving the various ocular muscles. 3. The disposition and number of crossed and bilateral innervations.
OCULOMOTOR NERVE REGENERATION
Animal experimentation poses various influences for consideration which might ac count for some of the diverse conclusions. They are : 1. Time of study after operation. Cells disappear after too long a time following damage and it is better to study the degener ating cell than no cell at all. 2. Nature of the lesion—severing, crush ing, inflammation, etc. 3. Distance of lesion from the nucleus. 4. Difference in species. 5. The age of the subject. Crosby states2 "Discrepancies in tech nique must await further facts for their res olution for it is evident that little is to be gained by conjecture in the present state of knowledge concerning the integration of the ocular musculature." Generally speaking, with damage to the nerve in the monkey (Macaca mullata), after 10 days the oculomotor nuclei are affected, showing chromatolysis or other ev idence of degeneration affecting about 40% of the entire ipsilateral nucleus and 10% of the contralateral nucleus in which the lower third is chiefly involved. This degenerative process continues until chromatolysis is at its maximal stage, about 30 days (some au thors say half this time). If there is to be recovery, regeneration appears to be insti tuted at this time in the intraorbital and intracranial nerve and the nucleus. More recent investigators reported crossed connections to the troclear and abducens nuclei and less crossings have been advocated to the oculomotor nuclear compo nents. Warwick 3 states that the elevators of both lids have a common medial pool (in the monkey, in the caudal portion of the central nucleus serving both levator muscles). He found that after one levator nerve was de stroyed only half of the nucleus was affect ed and contralateral chromatolytic changes were found. He also found changes in the contralateral area serving the superior rectus muscle and in no other contralateral areas.
1241/301
PRESENT EXPERIMENT
The right oculomotor nerve was severed intracranially in the middle fossa in eight monkeys without trauma to adjacent struc tures. The severed ends were separated by less than a mm. A complete third-nerve pa ralysis resulted, with dilated pupil, ptosis and extraocular paralysis, save for the sixth and fourth innervated muscles. In three weeks following operation, there developed the beginning of a teeter-totter of the upper lids which persisted for several weeks with very little change. When the monkey looked to the left, the right lid was raised (pseudo-Graefe sign) and the left lid lowered. When the monkey looked to the right the ptosis of the right lid reappeared and the palpebral space on the left side was widened. Looking from side to side the teet er-totter was seen (fig. 1). The pupil of the operated side remained fairly well dilated during this period. After six weeks, the teeter-totter phenomenon became less evi dent, possibly as regeneration progressed, sometimes to normal (four months except ing pupil size and reaction), subnormal (persistent) or, possibly, other aberrant types of function, which were demonstrated by the pseudo-Graefe phenomenon or Gower's sign (1879), or Fuchs' sign (1893), in which the upper lid is elevated, widening the palpebral space with efforts of adduc tion and inf raduction. With the effort to place the eye in any of the directions served by the muscles inner vated by the oculomotor nerve through en masse stimulation, there was in the affected eye upon attempted adduction : 1. Equally opposed vertical muscle stimu lation and, therefore, no, or very slight, ver tical movement. 2. Some adduction from unopposed medi al rectus muscle with relaxation of the later al rectus (abducens). 3. Elevation of the upper lid from unop posed stimulation of the levator muscle with widening of the palpebral space (pseudoGraefe sign).
1242/302
DONALD J. LYLE
4. Upon abduction, with abducens stimu lation, ptosis was re-established and all other oculomotor action suppressed. 5. T h e pupil may or may not contract on adduction and dilate on abduction. This phenomenon in part (that is, the lid
movement) is reversed by the opposite eye which, although its third nerve remains in tact, manifests the same type of levator muscle reaction, which confirms Warwick's conclusion of a common levator pool. This en masse stimulus appeared to be so
Fig. 1 (Lyle). Ocular findings in monkey after right oculomotor nerve was severed intracranially in the middle fossa without trauma to adjacent structures. (Upper left) Looking right. (Upper right) Look ing forward. (Lower left) Looking left. (Lower right) Looking far left.
OCULOMOTOR NERVE REGENERATION dominating that only with great difficulty were we able to have the monkey look to the right side with the functioning abducens (the lateral rectus muscle), which one would believe would actually be the position of preference or of rest. T h e monkey pre ferred to keep looking to the left with ptosis of the left lid, so much so that those ob servers who did not know which side was operated believed the left oculomotor was cut and not the right. All the monkeys be haved in this manner. Clinical studies of oculomotor degenera tion and regeneration are, for obvious rea sons, incomplete. These animal experiments present a more complete study in that they have been observed from the sectioning of the oculomotor nerve in the middle fossa to the autopsy examination of the oculomotor nuclei.
1243/303
tigation of regeneration of peripheral and other cranial nerves, in addition to clinical evidence reported here and elsewhere, to as sume this is an "en masse" reaction with "all or none" response, with loss of the specific predestined individual muscular in nervation from a nuclear cell group. This is evidenced consistently in the pres ent experiment, in the monkeys studied, in the reaction of the extraocular muscles served by the oculomotor nerve. T h e intra ocular muscles, the dilator of the pupil and ciliary, appear to respond in lesser degree to regeneration and stimulation. Finally, I should like to state that this study might be termed a concept and not an established fact. It requires further investi gation, especially in its application to hu mans. 411 Oak Street (19). REFERENCES
CONCLUSION
N o one, to my knowledge, has ever traced an aberrant axon from its specific cellular location in the oculomotor nucleus to its muscular innervation, proving the assump tion of its misdirected course. It appears to me more reasonable, and with supporting evidence from recent inves
OPHTHALMIC
1. Bender, M. B., and Fulton, J. F. : Functional recovery in ocular muscles of a chimpanzie after section of the oculomotor nerve. J. Neurophysol. 1:144,1938. 2. Crosby, E. C, Humphrey, T., and Lauer, E. W. : Correlative Anatomy of the Nervous System. New York, Macmillan, 1962, p. 242. 3. Warwick, R. : In the Oculomotor System. (Ed ited by Bender, M. B.) New York, Hoeber, 1964 p. 173-204.
MINIATURE
Those who are unacquainted with the anatomy of the eye can only acquire this knowledge perfectly by dissections, which should be repeated on the dead eyes of animals ; but particularly of the human subject. A few dissections will impress the mind with more complete ideas of the eye than a thousand written descriptions. A Treatise on 118 Principle
Diseases of the Eyes and Eyelids William Rowley, London, 1790