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Posttraumatic Abducens to OculomotorNerve Misdirection

dward G. Buckley, MD, Forrest D. Ellis, MD, Eric Postel, MD, and Timothy Saunders, MD

ntroduction: Paradoxical patterns of extraocular muscle, eyelid, or pupillary movements can occur followingnjury between divisions of the oculomotor nerve, trigeminal and abducens nerves, and trigeminal and oculomotorerves. We report three cases of unusual ocular motility and eyelid movements that are a result of aberrantonnections between the abducens and oculomotor nerves. Methods: Three patients with unusual eye movementbnormalities after trauma were studied. A complete ophthalmic examination plus neuroradiologic evaluationere performed. Results: Each patient manifested an aberrant connection between the 6th and 3rd cranial nerves

esulting in third nerve function during sixth nerve stimulation. Two patients demonstrated complete third nervealsies except for adduction on attempted abduction. The third showed improved bilateral ptosis on abduction.onclusions: The neuroanatomical abnormalities involve intraorbital structures in one patient and central nervousystem pathways in the others. Explanations such as retrograde regeneration, ephaptic transmission, or dener-ation supersensitivity do not appear to explain these unusual eye movements. The most likely mechanismnvolves some form of peripheral neuronal misdirection. These rare sixth to third nerve misdirection cases addupport to the “neuronal misdirection hypothesis” of aberrant eye movements after trauma. (J AAPOS 2005;9:

2-16)

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aradoxical patterns of extraocular muscle, eyelid, orpupillary movements can occur congenitally or maydevelop following injury to ocular motor nerves

hree, four, and six from trauma, tumor, or aneurysm.1-5 Inuch cases certain muscle groups are innervated by cranialerve fibers which are normally destined for other mus-les.6 This abnormal innervation can occur in addition to,r instead of, the normal pattern. The proposed mecha-isms include peripheral nerve redistribution, interneuro-al ephaptic transmission, central reorganization, and de-ervation hypersensitivity.7,8 Of these mechanisms, theost commonly accepted is the redirection of the regen-

rating sprouts of the injured peripheral neurons to inner-ate inappropriate muscle groups resulting in abnormalye movements. These aberrant connections have beeneported between divisions of the oculomotor nerve,9 tri-eminal and abducens nerves,10,11 trigeminal and oculo-otor nerves, and abducens and oculomotor nerve.12 We

eport three cases of unusual ocular motility and eyelidovements that are the result of aberrant connections

etween the abducens and oculomotor neuronal systems.

rom the Duke University Eye Center, Durham, NC.ubmitted March 9, 2004.evision accepted November 10, 2004.eprint requests: Edward G. Buckley, MD, Duke University Eye Center, Box 3082,urham, NC 27710opyright © 2005 by the American Association for Pediatric Ophthalmology andtrabismus.091-8531/2005/$35.00 � 0

doi:10.1016/j.jaapos.2004.11.011

2 February 2005

ASE REPORTS

ase 1

25-year-old female suffered a stab wound to her rightuperior orbit. She had normal eye movements prior to therauma. Immediately after the injury, she had a completephthalmoplegia and ptosis. On examination 3 monthsater, her best corrected visual acuity was 20/100 OD and0/30 OS. There was a 4-mm right upper lid ptosis withoor levator function. The right pupil was 8 mm andonreactive. There was no afferent pupillary defect. Ocu-

ar motility testing showed a 15 prism diopter esotropia inhe primary position at both 20 feet and 13 inches fixation.n duction testing, the right eye did not move on adduc-

ion, elevation, and depression but, on attempted abduc-ion, the eye would fully adduct and the lid would elevateFigure 1). There was no pupillary change noted in eitherye while the right eye was adducting indicating the ab-ence of convergence substitution. The right eye wouldot adduct on attempted convergence. Forced ductionesting was negative. The remainder of her examinationas normal except for some mild right optic atrophy. The

ituation remained unchanged for 4 years.

ase 2

previously healthy 31-year-old man sustained a frontalkull fracture in a motor vehicle accident (MVA). He wasomatose for 8 weeks. Ophthalmic examination was per-ormed after he regained consciousness. His best correctedisual acuity was LP OD and 20/50 OS. The right pupil

iameter was 7 mm and nonreactive, and a right afferent

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Journal of AAPOSVolume 9 Number 1 February 2005 Buckley et al 13

upillary defect was present. There was a right upper lidtosis of 5 mm with poor levator muscle function. Ocularotility testing showed a small exotropia in the primary

osition with a complete ophthalmoplegia of the right eyexcept, on attempted right gaze, the right eye adductednd the ptotic lid elevated (Figure 2). Neither pupil con-tricted, indicating the patient was not using convergenceo make the eye adduct (convergence substitution) and noovement of the right eye occurred on attempted conver-

ence, confirming a peripheral nerve, as opposed to aupranuclear, injury. Fundus examination revealed optictrophy OD.

ase 3

previously healthy 12-year-old female suffered a closedead injury during a MVA. Ophthalmic examination im-

IG 1. Case 1: Ocular rotations show that the right eye did not moven adduction, elevation, and depression but, on attempted abduc-

ion, the eye would fully adduct and the lid would elevate. Bottom:here was no adduction on convergence.

IG 2. Case 2: Ocular motility testing showed a small exotropia in therimary position with a complete ophthalmoplegia of the right eyexcept, on attempted right gaze, the right eye adducted and thetotic lid elevated. On left gaze there was no adduction of the rightye.

ediately after the accident revealed a complete bilateral f

tosis and ophthalmoplegia. Magnetic resonance imagingcan showed a focal midbrain lesion near the red nucleus.our months later her visual acuity was 20/20 OU. Heright pupil remained fixed and dilated; her left pupil re-cted to light, and both reacted poorly to convergence.here was a bilateral 5-mm ptosis with no levator functionn up gaze. Ocular motility evaluation demonstrated exo-ropia of 20 prism diopters in the primary position. Onight gaze, both lids fully elevated (Figure 3). Up gaze, leftaze, and down gaze were minimally limited and had noffect on her ptosis. She preferred a right gaze position tomprove the lid position. This situation remained stableor 1 year. She subsequently underwent a Kestenbaum-liketrabismus operation13 to enhance her lid elevation andliminate her exotropia.

ISCUSSION

berrant neuronal connections between the cranial nervesf the oculomotor control system can be congenital orcquired.14-18 Congenital entities such as Marcus Gunnaw winking, synergistic divergence, and Duane syndromere thought to result from an abnormal wiring of thisystem.19 In these situations cranial nerve fibers are mis-irected from their normal target to supply innervation totructures that have been denervated due to some devel-pmental abnormality. For example, in Duane syndromeome of the medial rectus nerve fibers (oculomotor nerve)re supplying the denervated lateral rectus (abducenserve). Clinically, there is absent or markedly reduced

ateral rectus muscle function plus a characteristic globeetraction seen on attempted adduction due to simulta-eous medial and lateral rectus muscle innervation.

While congenital miswiring between the cranialerves serving the oculomotor control system is fairlyommon, acquired cases are relatively rare.10 Jordan etl described a patient who had unilateral palpebral fis-ure widening on abduction with normal lateral rectus

IG 3. Case 3: Ocular motility evaluation showed an exotropia of 20D in the primary position. On right gaze both lids fully elevated. Upaze, left gaze, and down gaze were minimally limited and had noffect on her ptosis.

unction following severe head trauma. They hypothe-

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Journal of AAPOSVolume 9 Number 1 February 200514 Buckley et al

ized that the sixth cranial nerve fibers were innervatinghe levator muscle resulting in lid elevation on at-empted abduction of the eye.12 An aberrant connectiont the superior orbital fissure was postulated as the causef the abnormal movements. Pfeiffer et al described aase where right pupillary constriction occurred only onight gaze. This was felt to be due to misdirection ofegenerating fibers of the right abducens nerve into thearasympathetic pathways of the right oculomotorerve.20 Packer and Bienfang described a case of aber-ant regeneration involving the abducens and oculomo-or nerves in a patient following severe head trauma.21

heir patient had complete ophthalmoplegia of theight eye with no movement; except on attempted ab-uction, the right eye adducted. There was no associ-ted lid elevation, but the ptosis did improve on at-empted down gaze (“Pseudo-Graefe” sign).

Several theories have been proposed to explain thisnusual phenomenon of acquired ocular motor misdirec-ion.12 The most common acquired eye muscle misdirec-ion syndrome involves the structures innervated by aingle cranial nerve, the oculomotor nerve (aberrant re-eneration of the third nerve, acquired oculomotor syn-inesis), and is manifested by abnormal patterns of pupil-ary, lid, and ocular movements that develop followingculomotor nerve paralysis.22 Bielschowsky suggested thathis may be due to peripheral misdirection of oculomotorbers (“misdirection hypothesis”).6 Fibers in the oculomo-or nerve which were destined to innervate the medialectus were “misdirected” after injury to also supply theevator muscle, resulting in lid elevation on attempteddduction (Pseudo-Graefe sign).23 Cajal, working with aat sciatic nerve, showed that during the repair processewly formed nerves can grow randomly into distal stumpsventually innervating the wrong muscles.24 Therefore its possible that this synkinesis could result from either anerve-to-nerve” or a “nerve-to-muscle” misconnection.

The misdirection hypothesis is not universally acceptedespite supportive clinical evidence. One of the greatesturdles to acceptance is the existence of cases of reversibleynkinesis. Reversibility has been documented in at leastwo cases of acquired oculomotor synkinesis.25 An impor-ant alternative to the misdirection hypothesis involvesphaptic transmission or side-to-side interaxonal crosstimulation.19,26,27 This mechanism has also been pro-osed to explain hemifacial spasms and gustatory lacrima-ion.28 However, ephaptic transmission has not been dem-nstrated in the third nerve. A third theory, proposed byuchs, states that peripheral nerve injury induces retro-rade changes that result in CNS reorganization. Thisentral reorganization presumably produces synkinesis bynmasking previously encoded connections in the brain-tem or higher control center areas. CNS plasticity mayllow a return to the previously normal state and thusxplain the reversibility of the synkinesis.12 The charac-

eristic convergence retraction nystagmus seen in periaq- p

eductal lesions of Parinaud’s syndrome is an example of aentral mechanism that anomalously synchronizes the mo-or output from structures in both the pons (horizontalaze) and the midbrain (vertical gaze).

The mechanism for the abnormal eye movements inur cases can be best explained by some form of theeuronal “misdirection hypothesis.” Clearly in case 1,here was local trauma to the orbit without involvementith other cranial structures. The third and sixth nerve

unctions were completely disrupted and function was en-irely absent except when the abducens nerve was signaled,hich resulted in medial rectus muscle contracture rather

han the lateral rectus muscle. It appears as if the abducenserve “reconnected” with the branch of the oculomotorerve supplying innervation to the medial rectus musclend the lid (Figure 4). The absence of any convergence ofhis eye confirms that all the normal connections to theedial rectus muscle by the third nerve are no longer

resent. If ephaptic transmission were occurring, it muste a complete “jump” of the signal from one nerve to thether with none of the normal signal reaching the in-ended target. Another interesting possibility is some formf central “misdirection” as outlined in Figure 5 and pos-ibly supported by case 2.

Case 2 has the same clinical picture as case 1, but thereas no local trauma to the orbit and therefore no obviousirect injury to the third and sixth nerves. Here the dis-uption must have occurred at the level of the orbital apexr cavernous sinus where the nerves could have beenamaged from the sheer force of the injury. While the

IG 4. Schematic illustrating the proposed neural misdirection in theight orbit for case 1. Note the abducens nerve is innervating theedial rectus and levator muscle of the right eye. VI � sixth nerveucleus, III � third nerve nucleus.

resence of optic atrophy on the involved side suggests

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Journal of AAPOSVolume 9 Number 1 February 2005 Buckley et al 15

hat the disruption did occur in the area of the orbital apex,here were no visible fractures at this location and otherranial nerves outside this region were involved. Anotherossibility is injury more centrally in the brainstem. Givenhe amount of other cranial nerve dysfunction (trigeminal,acial), it is possible that the brainstem, at the level of theons, was severely injured, resulting in disruption of theormal “internuclear connections” between the third andixth nuclei. The gaze signal, instead of traveling up theontralateral medial longitudinal fasciculus to the con-ralateral medial rectus subnucleus, is diverted up therong MLF to the ipsilateral third nerve (Figure 5). In

ddition, the sixth nerve fascicle would have to be discon-ected or the nucleus damaged to inhibit lateral rectusunction. The net result would be as seen in our patients,hich is adduction occurring with attempted abduction.he fact that no other third nerve function could be

licited in either of these two cases without attemptingbduction of the involved eye strongly suggests a moreeripheral misdirection.

Both cases 1 and 2 had abnormal lid elevation whichppeared like a typical aberrant third nerve synkinesisxcept for the fact that the movement was occurring onttempted abduction not adduction. There are two possi-le explanations for this lid elevation. One is that thebducens nerve is hooking up directly to the levatorranch along with the medial and the other is that there issecond area of misdirection in the third nerve different

rom the abducens nerve hookup (ie, abducens nerve toedial branch to levator). The latter mechanism is sup-

orted by the case described above reported by Packer andienfang.21 It is possible that in severe trauma a “step-

adder” type of ocular motor misdirection may develop.Case 3 can also be explained by peripheral misdirection

henomena but requires combining two separate injuries:

IG 5. Schematic illustrating the theoretical neuronal miswiring inhe brainstem required to give the ocular motility findings of case 2.he right parapontine reticular formation (PPRF) is stimulating theight medial longitudinal fasiculus (MLF) instead of the left. Thisesults in adduction of the right eye on attempted right gaze. Theormal pattern shown by the dotted lines is not functional. MR �edial rectus, LR � lateral rectus, VI � sixth nerve nucleus, III �

hird nerve nucleus.

he right eye has an injury similar to those described above

ith the abducens nerve connecting to the levator causinglevation on attempted abduction of the right lid and theeft has a more typical misdirection of the left medial nerveranch to the levator resulting in elevation of the left lidn adduction. This would give the appearance of both lidslevating only on right gaze. A plausible alternative expla-ation would require an injury to the brainstem with aentral misdirection of the horizontal gaze signal to theevator subnucleus. Since both lids only elevated fromheir normal ptotic position on attempted right horizontalaze, it is postulated that the signal must have reached theentral caudal nucleus controlling the levator muscle fromhe right gaze center (sixth nerve nucleus) through the

LF (Figure 6). Lepore and Glaser have proposed aimilar mechanism where acquired oculomotor nerve syn-inesis actually occurs within the oculomotor nerve sub-uclei at the central level rather than peripherally.29 Ourase possibly supports this theory. The first explanationas the advantage of providing a common mechanism forll three cases, but the second explains why there is noignificant limitation in ocular movement in any direction.

References1. Keane JR. Bilateral aberrant regeneration of the third cranial nerve

following trauma. J Neurosurg 1975;43:95-7.2. O’Day J, Billson F, King J. Ophthalmoplegic migraine and aberrant

regeneration of the oculomotor nerve. Br J Ophthalmol 1980;64:534-6.

3. Kerns JM, Smith DR, Janotta FS, Alper MG. Oculomotor nerveregeneration after aneurysmal surgery. Am J Ophthalmol 1979;87:225-33.

4. Schatz NJ, Savino PJ, Corbett JJ. Primary aberrant oculomotorregeneration: a sign of intracavernous meningioma. Arch Neurol1977;34:29-32.

5. Sebag J, Sadun AA. Aberrant regeneration of the third nerve follow-ing orbital trauma: synkinesis of the iris sphincter. Arch Neurol1983;40:762-4.

6. Bielschowsky A. Lecture on motor anomalies of the eyes. Arch

IG 6. Schematic illustrating the theoretical neuronal brainstemiswiring for case 3. On right gaze the central caudal nucleus (CNN)hich controls both lids is stimulated along with the left medial

ectus muscle through the medial fasiculus (MLF). MR � medialectus, LR � lateral rectus, VI � sixth nerve nucleus, III � thirderve nucleus, PPRF � parapontine reticular formation.

Ophthalmol 1935;13:33-59.

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7. Sibony PA, Lessel S, Gittinger JW. Acquired oculomotor synkinesis.Surv Ophthalmol 1984;28:382-90.

8. Gowers WR. The movements of the eyelids. Med Chir Trans 1879;62:429-40.

9. Boghen D, Chartrand JP, Laflamme P, et al. Primary aberrant thirdnerve regeneration. Ann Neurol 1979;6:415-8.

0. Nelson SK, Kline LB. Acquired trigemino-abducens synkinesis.J Clin Neuroophthalmol 1990;10:111-4.

1. McGovern ST, Crompton JL, Ingham PN. Trigemino-abducenssynkinesis: an unusual case of aberrant regeneration. Aust NZ JOphthalmol 1986;14:275-9.

2. Jordan DR, Miller DG, Anderson RL. Acquired oculomotor—abducens synkinesis. Can J Ophthalmol 1990;25:148-51.

3. Kestenbaum A. Nouvelle operation du nystagmus. Bull Soc Ophtal-mol Fr 1953;53:599.

4. Guy M, Engel HM, Lessner AM. Acquired contralateral oculomotorsynkinesis. Arch Neurol 1989;46:1021-3.

5. Cox TA, Wursten JB, Godfrey WA. Primary aberrant oculomotorregeneration due to intracranial aneurysm. Arch Neurol 1979;36:570-1.

6. Krohel GB. Blepharoptosis after traumatic third-nerve palsies. Am JOphthalmol 1979;88:598-601.

7. Ford FR, Woodhall B. Phenomena due to misdirection of regener-ating fibers of cranial, spinal and autonomic nerves: clinical obser-vations. Arch Surg 1938;36:480-96.

8. Chorobski J. Syndrome of crocodile tears. Arch Neurol Psychiatry

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9. Miller NR. Walsh and Hoyt’s Clinical Neuroophthalmology, 4th ed.Baltimore (MD): Williams & Wilkins; 1991. p. 676-82.

0. Pfeiffer N, Simonsz HJ, Kommerell G. Misdirected regeneration ofabducens nerve neurons into the parasympathetic pupillary pathway.Graefes Arch Ophthalmol 1992;230:150-3.

1. Packer AJ, Biefnang DC. Aberrant regeneration involving theoculomotor and abducens nerves. Ophthalmologica 1984;189:80-5.

2. Forster RK, Schatz NJ, Smith JL. A subtle eyelid sign in aberrantregeneration of the third nerve. AJO 1969;67(5):696-8.

3. Bender MB. The nerve supply to the orbicularis muscle and thephysiology of movements of the upper lid: with particular referenceto the pseudo-Graefe phenomenon. Arch Ophthalmol 1936;15:21-30.

4. Ramon Y, Cajal S. In: May RM, ed. Degeneration and Regenerationof the Nervous System. London: Oxford Press, 1928.

5. Johnson LN, Pack WL. Transient oculomotor nerve misdirection ina case of pituitary tumor with hemorrhage. Arch Ophthalmol 1988;106:584-5.

6. Seltzer K, Devor M. Ephaptic transmission in chronically damagedperipheral nerves. Neurology 1979;29:1061-4.

7. Tomasulo RA. Aberrant conduction in human peripheral nerve:ephaptic transmission? Neurology 1982;32:712-9.

8. Gardner WJ, Sava GA. Hemifacial spasm. A reversible patholophysi-ologic state. J Neurosurg 1962;19:240-7.

9. Lepore FE, Glaser JS. Misdirection revisited: a critical appraisal ofacquired oculomotor nerve synkinesis. Arch Ophthalmol 1980;98:

2206-9.

An Eye on the Arts – The Arts on the Eye

I sat down on the side of the bed, trying to contain my excitement so as notto give anything away. When my father had propped himself up on two pillowsand we sat facing each other, I said as simply as I could, “Pop, I made it. I’mgoing to be chief resident.” He looked blankly at me for an instant, as thoughnot comprehending the import of what was being said. Then his expressionslowly changed as all his lifelong hopes began to shine forth from his eyes andinto mine. I had done this great thing for all the reasons that make young menstrive for success, but I had done it for him. This is what those luminous eyeswere telling me. What I saw in his face was something beyond pride. It wasvindication; it was fulfillment; it was love of a father for his son—a father whowas just beginning to learn how to express his depth of feeling.

I threw my arms around Pop’s shoulders and made no attempt to disguise thetears. After long and emotional seconds of holding him to me and being held tohim, we slowly let go of each other. At that moment, I saw that his eyes—thosewonderful soulful eyes that said so much—were now beyond shining. Theywere lustrous. I saw long years of the past in them, and I saw the presentmoment of realization, in which the strands of our lives had come together ina kind of awe. I thought I could see the future. I looked into the face of myfather, and saw everything there.

—Sherwin B. Nuland (from Lost in America: A Journey with My Father)