Journal of Neuro-Ophthalmology, December 1994, Volume 14, Issue 4

Ocular motor systems.

Journal of Neuro- Ophthalmology 14( 4): 224- 233, 1994. © 1994 Raven Press, Ltd., New York Annual Review: Ocular Motor Systems Part 1: Infranuclear Systems Barry Skarf, Ph. D., M. D. This review covers selected articles dealing with the physiology of eye movements and their disorders which appeared in the world medical and scientific literature during 1993. The subject matter and the review have been divided into two parts. Presented here is a review of papers concerned with infranuclear systems: periph­eral nerves ( oculomotor nerve, trochlear nerve, abducens nerve, multiple ocular motor palsies) and eye muscle and orbit ( ocular myasthenia gravis, dysthyroid ophthalmop­athy, chronic progressive external ophthalmoplegia, miscellaneous diseases of eye muscle, and methodol­ogy)- Part 2, dealing with supranuclear systems, will appear in a subsequent issue of this journal. PERIPHERAL NERVES Oculomotor Nerve Aneurysms arising at the junction of the poste­rior communicating and internal carotid arteries are closely related to the third nerve. They may present with ipsilateral fronto- orbital pain with or without associated third nerve palsy. In a study of human autopsy material ( 1) sensory ganglion cells were found within the rootlets of the oculomotor nerve. Parallel animal studies ( 1) demonstrated that sensory fibers from the ophthalmic division of the fifth nerve join the third nerve within the lat­eral wall of the cavernous sinus and run proxi-mally along the nerve bundles to enter the brain­stem and reach the spinal trigeminal nucleus. The authors of this anatomic study argue that the fron­to- orbital pain experienced by patients with en- From the Neuro- ophthalmology Unit, Henry Ford Health Sci­ences Center, Detroit, Michigan, U. S. A. Address correspondence and reprint requests to Dr. Barry Skarf, Neuro- ophthalmology Unit, Henry Ford Health Sciences Center, 2799 West Grand Boulevard, Detroit, MI 48202, U. S. A. larging aneurysms could be caused by direct irri­tation of the third nerve. This study is the latest in a series of papers demonstrating trigeminal affer­ent fibers in the oculomotor nerve in man and mammals. In a letter to the editor, members of this research team suggest that ischemic damage to the trigeminal fibers in the oculomotor nerve may also be the source of pain in ischemic- diabetic third nerve palsies ( 2). The normal physiologic function of these sensory fibers and the absence of pain with other causes of oculomotor lesions within the cavernous sinus remain unanswered questions. As part of ongoing studies of the topographical organization of the oculomotor nerve fibers inner­vating individual extraocular muscles in the rat, those axons innervating the superior rectus were localized to the dorsal part of the nerve ( 3). In the proximal part of the nerve there was a slight dor­solateral extension of the fiber bundle and in the more distal sections the axons were distributed more dorsomedially. Thus, the topographic orga­nization of the subdivisions of the third nerve, which has been demonstrated at a nuclear and fas­cicular level continues along the peripheral nerve until its anatomic bifurcation into superior and in­ferior divisions. Keane ( 4) reviewed his series of 815 patients with third nerve palsies and found that 20 of the patients had penetrating trauma, usually as a re­sult of a gunshot wound. Direct injury to the third nerve nerve occurred anywhere along its course from the brainstem to the orbit, and all 20 patients developed immediate palsies. Closed head injuries frequently produce sixth nerve palsies, but third nerve palsies following mi­nor head trauma occur much less frequently. Bilat­eral total third nerve palsies appeared in a 51- year-old man who fell 12 ft ( 5). Computed tomography 224 ANNUAL REVIEW- EYE MOVEMENTS 225 ( CT), magnetic resonance imaging ( MRI), and an­giography were normal. The patient later devel­oped aberrant regeneration of both oculomotor nerves. The authors review the literature and dis­cuss the probable pathogenesis and site of the le­sion. Ophthalmoplegic migraine involving the third nerve transiently is a well- known entity. With the advent of gadolinium contrast, MRI lesions of the cranial nerves can be demonstrated neuroradiolog-ically. A single case of ophthalmoplegic migraine in which there was proximal enhancement of the third nerve at its point of exit from the brainstem on MRI has been documented ( 6). No other lesion of the brainstem or of the third nerve along its distal course through the cavernous sinus and into the orbit was found. In a comprehensive review of ophthalmic com­plications arising from orthognathic surgery, both sensory and ocular motor complications are de­scribed, along with neuroparalytic keratitis and problems involving the lacrimal apparatus ( 7). Di­rect injuries resulting from the osteotomies are most unlikely, and the presumed cause of the un­expected cranial nerve palsies is indirect injury to neurovascular structures supplying the affected nerve. Also, nerve damage can occur when frac­ture lines extend from the facial bone to include foramina containing neurovascular structures. In addition to their review and discussion of etiolo­gies, eight new cases are reported: three with vi­sual loss, three with dry eyes due to lacrimal in­sufficiency, and two with epiphora due to nasolac­rimal duct obstruction. Although no new cases of ocular motor palsies are reported, the review in­cludes descriptions of isolated third nerve and sixth nerve palsies and of an Adie's pupil. Isolated oculomotor nerve palsies were de­scribed in patients with a variety of cavernous si­nus abnormalities ( 8- 11). A third nerve palsy caused by a cavernous angioma arising from the substance of the nerve was described in a patient with Roberts syndrome ( SC phocomelia) ( 8). The association of a cavernous angioma of the third nerve with Roberts syndrome is not unique. An earlier case report describes a similar intrinsic cav-ernoma of the cauda equina in a patient with Rob­erts syndrome ( 12). The relationship between these two rare and unusual conditions is unclear. An intracavernous dermoid occurred in a 4- year-old boy who presented with a pupil- sparing third nerve palsy ( 9). Five patients are described who developed third nerve palsies with dural cavern­ous sinus fistulas ( 10), but this was the initial symptom in only one of these patients. The other four patients presented with orbital pain. Two of the patients had normal pupil responses, two had complete internal and external third nerve palsies, and the fifth had a partial external paresis with a sluggish pupil. Two patients were treated with embolization and hemostatic agents, two went un­treated, and a third was treated only with hemo­statics. All recovered excellent oculomotor func­tion. The authors emphasized that the conjunctiva appeared normal in all of these patients and that there were no other ocular signs of cavernous fis-tulae. This study ( 10) suggests that some patients who are thought to have ischemic third nerve le­sions, who do not undergo angiography, may have low- pressure dural cavernous fistulae that re­solve spontaneously. Autopsy of patient with idiopathic thrombocy­topenic purpura, who developed a third nerve palsy ( 11), revealed intraneural hemorrhage of the cavernous portion of the third nerve. While intra­neural hemorrhages have been reported in pa­tients with hemorrhagic diatheses, this case is the first to document cranial nerve involvement. Two patients with AIDS and cryptococcal men­ingitis developed episodic, intermittent third nerve palsies associated with fluctuating, elevated intracranial pressure ( 13). CT scans obtained on both patients ruled out tentorial herniation as a cause of the oculomotor palsy. The author specu­lates that infectious invasion of the affected nerves predisposed them to the effects of elevated intra­cranial pressure, which was the immediate cause of the transient palsy. A similar effect of intermit­tent intracranial pressure elevation has been ob­served on the sixth nerve ( 14). One other case of a complete third nerve palsy associated with benign intracranial hypertension has been described ( 15), but this presumed effect of elevated intracranial pressure on the oculomotor nerve must be exceed­ingly rare. Burkitt's lymphoma can be added to the causes of pupil- sparing third nerve palsies, as docu­mented in the case of an 11- year- old girl who pre­sented with painful ophthalmoplegia ( 16). This patient improved transiently on a course of dexa-methasone, but when the steroids were with­drawn she developed multiple bilateral cranial nerve palsies and was found to have a large supra-and parasellar mass. The authors remind us that lymphoma can be mistaken for the Tolosa- Hunt syndrome, but, unfortunately, they do not have histopathologic specimens from the middle fossa. The diagnosis is based on biopsy of an abdominal mass. Since the patient died 1 month later with Candida albicans sepsis, and autopsy was refused, / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 226 B. SKARF the exact nature of the intracranial mass remains presumptive. An 80- year- old woman developed an isolated palsy of the superior branch of the oculomotor nerve attributed to sphenoid sinusitis, which had eroded into the optic canal ( 17). The patient recov­ered completely after drainage of the sinus. How­ever, considering the patient's age and the fact that she had hypertension, the etiology of the palsy and the contribution of the sinusitis to its patho­genesis is uncertain. Trochlear Nerve Brazis ( 18) has written a comprehensive review on the diagnosis and localization of fourth nerve palsies. He emphasizes the use of the Maddox Rod and the Bielchowsky head tilt test and the mea­surement of excylotorsion with the Double Mad­dox Rod test in order to differentiate superior oblique palsies from skew deviation and other causes of vertical diplopia. Spector ( 19) presents an excellent, comprehen­sive review of vertical diplopia, including the relevent anatomy, diagnostic techniques, and dif­ferential diagnosis. This paper contains excellent tables and a substantial bibliography. The author emphasizes the features that characterize supranu­clear, infranuclear, and restrictive disease. An isolated fourth nerve palsy was described in a patient with a mixed dural- pial arteriovenous malformation of the anterior cranial fossa ( 20). It was felt that the palsy was due to compression of the fourth nerve by a dilated orbital branch of the middle meningeal artery within the superior or­bital fissure. Lid retraction as component of aberrant regen­eration of the third nerve is well recognized. A case report that purports to document aberrant re­generation of the fourth cranial nerve in an elderly patient who developed traumatic third and fourth nerve palsies ( 21) seems to be nothing more than aberrant regeneration of the third nerve with very limited ocular motility. The authors appear to have missed the pupillary constriction that occurred when the patient gazed downward with the eye maximally adducted. While some fourth nerve fi­bers may have innervated the pupil and/ or the su­perior rectus there seems little reason to invoke this mechanism. Patients with plagiocephaly frequently have tor­ticollis. Some patients with plagiocephaly resulting from synostosis of the ipsilateral coronal suture have vertical strabismus and contralateral head tilt, mimicking fourth nerve palsies ( 22). Frontal pla­giocephaly can also be caused by external com­pressive forces acting on the skull either in utero, at birth, or perinatally. In these cases there are no abnormalities of the cranial sutures. In a review of 13 patients with deformation frontal plagiocephaly ( 23), 9 patients had torticollis. Seven of these had an ipsilateral head tilt, and 2 had a contralateral head tilt. None of the patients, however, had a vertical ocular motor imbalance or strabismus. One had a V- pattern exotropia with no evidence of oblique dysfunction. Since up to 80% of patients with synostotic plagiocephaly have a vertical stra­bismus, a feature not found in deformational pla­giocephaly, the ocular findings can be used to help distinguish between these two conditions. Abducens Nerve A review of 80 patients who underwent ventric­ular shunting for normal pressure hydrocephalus over a 12- year period uncovered three patients who developed abducens palsies within 2 weeks of surgery ( 24). This unusual complication had been reported only twice before. All except one case re­covered within 3 months. The mechanism pro­posed is similar to that for sixth nerve palsy which results from lumbar puncture: traction on the nerve resulting from displacement of the brain af­ter loss of cerebrospinal fluid. The use of MRI for the topographical localization of lesions to the sixth nerve in isolated sixth nerve palsies is reviewed and demonstrated in a series of illustrated cases ( 25). This paper emphasizes the need for a focused evaluation in order to study the entire course of the sixth nerve. Bilateral abducens palsies associated with other brainstem signs were caused by lesions in the mid-pontine tegmentum in two patients ( 26). Both pa­tients improved with time, but during the recovery phase both developed temporary pseudoathetosis of the hand contralateral to the side of the lesion. Three cases of sixth nerve palsy following cra­niofacial injury produced by blunt trauma to the side of the head were described ( 27). The injuries produced transverse fractures of the middle cranial fossa through the sphenoid sinus to the petrous apex. In all three cases the abducens palsy was associated with seventh and eighth cranial nerve dysfunction. The sixth and seventh nerve palsies resolved in all patients, but partial hearing loss persisted. An isolated acquired sixth nerve palsy due to an intracavernous carotid aneurysm is described in an 8- year- old girl ( 28). The authors consider the neu- / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 ANNUAL REVIEW- EYE MOVEMENTS 227 rosurgical and ophthalmological approach to this problem. In children, benign sixth nerve palsies, which occur following a viral illness, are a well- known entity. Two cases in which there were rising titers to Epstein- Barr virus were reported ( 29), presum­ably linking the abducens palsy to acute Epstein- Barr virus infection. In contrast, an 8- year- old boy who developed bilateral sixth nerve palsies and papilledema fol­lowing a middle ear infection was thought to have an underlying viral etiology causing his neuro-ophthalmic findings ( 30). When he failed to im­prove and suffered progressive visual loss, he was found to have a lateral transverse sinus throm­bosis and increased intracranial pressure. The authors cautioned that any child with a history of ear infection who develops papilledema and sixth nerve palsy should be evaluated for this con­dition. We are reminded that sixth nerve palsies, which may appear to develop following minimal head trauma, frequently are a sign of a space- occupying lesion by report of a case that was ultimately due to a schwannoma of the nerve within the cavernous sinus ( 31). All patients with sixth nerve palsy who do not begin to show recovery of function within three months should undergo MRI. On the other hand, some patients who develop sixth nerve palsies and diplopia due to slow-growing skull base tumors recover function spon­taneously with resolution of their diplopia. Seven cases of remitting sixth nerve palsy were reported in patients with neoplasm at the skull base ( 32). In most patients there were two or more such remis­sions, which occurred in the absence of any treat­ment. The authors discuss the possible mecha­nisms by which such recovery can occur. Because of this possibility, neuroimaging should be consid­ered in patients with sixth nerve palsy without vascular or inflammatory disease ( 32). Two patients with chronic severe headaches de­veloped isolated bilateral sixth nerve palsies and were found to have idiopathic hypertrophic cranial pachymeningitis ( 33). In both cases the diagnosis was elusive and was eventually proven by menin-gial biopsy. A third case with bilateral optic neu­ropathies is also included in this series, which brings to 10 the total number of cases of this con­dition described in the literature. All three patients described had thickened dura that enhanced with gadolinium on MRI and the authors emphasized the diagnostic usefulness of the distinctive MRI findings. In this condition, the histopathology demonstrates thickened, fibrotic dura with a ster­ile, chronic, nongranulomatous inflammation, and no evidence of arteritis. The article reviews the lit­erature emphasizing neuro- ophthalmic complica­tions, which include papilledema, optic neuropa­thy, and sixth and seventh nerve palsies. Other cranial nerves are also involved. The authors dis­cuss the diagnosis and differential diagnosis of this condition and the therapeutic approach to these patients, many of whom have suffered for months and even years with severe chronic headaches. Therapeutic modalities used include corticoste­roids, immunosuppression, and whole- brain radi­ation. Although neurosarcoidosis is known to involve the cranial nerves, an unusual case of a pseudoab-ducens paresis is described in which the lateral rectus function was compromised by a massively infiltrated lacrimal gland ( 34). The mechanical na­ture of the abducens dysfunction was demon­strated by a forced duction test. The problem re­solved with steroid therapy. The neural basis of Duane's retraction syndrome is now grossly understood based on electromyo­graphic and histopatholigic studies. Synergistic di­vergence is a similar condition involving apparent neural mis wiring. A profound adduction deficit with simultaneous abduction of both eyes on attempted gaze into the field of action of the affected medial rectus muscle characterizes this condition. Only 14 cases have been reported. The most recently reported case ( 35) was affected bilat­erally from birth. This patient had absolutely no adduction. The eyes were widely diverged, and any attempt at gaze to either side or to converge or focus increased the divergence. Vertical move­ments were present and the pupils were normal. In some cases cocontraction of the medial and lateral recti has been demonstrated, suggesting an innervational pattern similar to Duane type II syndrome. In this case, however, EMG of the me­dial recti were flat for all attempted movements. Thus, the exact nature of the miswiring disorder and of the underlying pathology remains un­known. Paradoxical EMG activity, characteristic of dual innervation of the medial rectus is described in four patients with Duane syndrome ( 36). The au­thors suggest that the syndrome may be associated with brainstem wiring anomalies and with anom­alous innervation of the medial rectus, in addition to absence or hypoplasia of the abducens nucleus. These wiring anomalies could account for the par­adoxical EMG activity recorded from both medial and lateral rectus muscles in some patients with Duane syndrome. / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 228 B. SKARF Multiple Ocular Motor Palsies An article directed to radiologists and ultra­sonographies reviews clinical terminology and manifestations associated with lesions of the skull base ( 37). This article would provide an excellent introduction to clinical manifestations of periph­eral neuro- ophthalmic disease for students on ro­tation in ophthalmology or neuro- ophthalmology and for residents beginning training in ophthal­mology or neurology. Fascination with painful ophthalmoplegia, fre­quently identified as Tolosa- Hunt syndrome, con­tinues in the literature. Three case reports which describe this condition in association with chronic hemodialysis ( 38), Hashimoto's thyroiditis ( 39), and with erosion of the sella ( 40) appeared in 1993. In each case, multiple ocular motor palsies were associated with intense ipsilateral orbital pain. All patients improved with corticosteroid therapy. In the patient on chronic hemodialysis ( 38), the au­thors emphasize the differentiation from second­ary amyloid neuropathy, which is prominent in the differential diagnosis of neuropathies in hemo­dialysis patients. The patient with Hashimoto's thyroiditis ( 39) underwent thyroidectomy 4 years prior to developing painful ophthalmoplegia. The authors argue that this association supports the view that Tolosa- Hunt syndrome and Hashimoto's thyroiditis may share a common underlying au­toimmune process. Sellar erosion has been de­scribed previously with Tolosa- Hunt syndrome and is attributable to the mass effect of the granu­loma ( 40). Confidence in the diagnosis in this case is based on steroid responsiveness of both CT and MRI findings, and particularly on the fact that the patient remained asymptomatic for 20 months af­ter steroid treatment was completed. Two patients with Tolosa- Hunt syndrome who had circulating antineutrophil cytoplasm antibod­ies ( ANCA) were presented in support of the the­ory that Tolosa- Hunt syndrome may be related to Wegener's granulomatosis ( 41). One of the pa­tients also had a history of Hashimoto's thyroid­itis. Both patients had a positive immunofluores­cence test for ANCA on ethanol fixed human granulocytes with a granular cytoplasmic pattern ( C- ANCA). These antibodies are mainly found in patient's with active Wegener's granulomatosis and microscopic polyarteritis. There was no sign of systemic vasculitis, but the positive laboratory studies suggest that Tolosa- Hunt syndrome may belong in the spectrum of the granulomatous vas-culitides such as Wegener's. An elderly man who presented with right- sided facial pain, visual loss, decreased ocular motility and proptosis was found to have a mass in the right orbital apex extending into the cavernous si­nus ( 42). The patient's condition worsened over 2 months, but the diagnosis remained elusive. The patient did have a history of CLL, stage 0, which had been treated 6 years previously. Ultimately, extraocular muscle biopsy disclosed leukemic infil­tration of the affected tissue. This paper, which is presented as a CPC, includes a detailed review of painful ophthalmoplegia/ cavernous sinus syn­drome. Another case of painful ophthalmoplegia in a 42- year- old woman who developed periorbital pain and a sixth nerve palsy progressed rapidly when she was given prednisolone therapy ( 43). Subsequently, she worsened and was found to have a fungal meningitis caused by Malassezia sp., which responded promptly to treatment with an­tifungal agents ( fluconazole and flucytosine). The effects and devasting consequences of mu­cormycosis are documented in a clinicopathologi-cal case report of an 86- year- old man who was hy­perglycemic and immunocompromised secondary to corticosteroid treatment ( 44). This report pro­vides useful review of rhinoorbitocerebral mucor infections. Global orbital infarction is described in three pa­tients who developed acute onset of blindness, or­bital pain, total ophthalmoplegia, and ischemia of both anterior and posterior segments ( 45). The ophthalmoplegia and anterior segment ischemia resolved with time, but the effects of ophthalmic artery occlusion persisted, and the patients re­mained blind. Thus, after the acute phase, these patients were indistinguishable from those who had suffered ophthalmic artery occlusion. The eti­ologies involved in these cases were occlusion of the common carotid, giant cell arteritis, and mu­cormycosis. EYE MUSCLE AND ORBIT Ocular Myasthenia Single fiber electromyography ( EMG) is abnor­mal in a high proportion of patients with myasthe­nia gravis. Unfortunately, in patients with exclu­sive ocular myasthenia recordings from skeletal muscle are not always abnormal. The usefulness of single fiber EMG performed on extraocular mus­cles was investigated in 42 patients with diplopia and/ or ptosis and in 11 controls ( 46). The diagnosis of myasthenia was based on observation of the pa­tients over a 5- year period and on their responsive- / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 ANNUAL REVIEW- EYE MOVEMENTS 229 ness to treatment with pyridosigmine bromide ( Mestinon). Single fiber EMG demonstrated an ab­normal jitter phenomenon in all myasthenic pa­tients. When compared to the Tensilon test and to titers of acetylcholine receptor antibodies, single fiber EMG was found to be much more sensitive in patients with exclusive ocular myasthenia. In this study, 24 patients had myasthenia, including 17 with pure ocular myasthenia. All had abnormal single fiber EMGs based on criteria defined in this paper. By the same criteria, all nonmyasthenic pa­tients and controls had normal single fiber EMGs. Thus, the authors conclude that this procedure may be the most sensitive and specific diagnostic test available for myasthenia. A letter verifying the diagnostic sensitivity of single fiber EMG of the orbicularis oculi muscle in patients with ocular myasthenia presents results from 14 patients and compares them to the results in 8 patients with chronic progressive external ophthalmoplegia ( 47). Results were pathologic in 13 of the 14 myasthenia patients and were normal in all 8 patients with chronic progressive external ophthalmoplegia. The authors point out that the sensitivity of this test is greater than that of the Tensilon test, repetitive nerve stimulation, or an-tiacetylcholine receptor antibodies. A very unusual case of procainamide- induced pseudomyasthenia gravis was described in a 64- year- old man who developed progressive weak­ness and chronic fatigue over several months ( 48). The patient had prominent ocular and generalized signs of weakness and fatiguability. In addition to his muscle weakness, the patient had a peripheral neuropathy. Curiously, the Tensilon test was neg­ative. These last two observations were also found in the only other reported case of pseudomyasthe­nia due to procainamide. The patient showed dra­matic improvement after the drug was discontin­ued. Thus, the combination of a negative Tensilon test and a peripheral motor neuropathy should alert the clinician to inquire as to procainamide in­gestion. If this drug is being used by the patient, the possibility of procainamide- induced myasthe­nia should be evaluated by judicious discontinua­tion of the drug ( 48). Two papers described differences in the antibod­ies against eye muscle in ocular, as opposed to generalized, myasthenia gravis ( 49,50). Autoanti­bodies against proteins in skeletal and extraocular muscle were analyzed from sex- and age- matched groups of patients with either generalized or ocu­lar myasthenia. Several antibodies were present in the generalized group that were not present in the ocular myasthenia group and vice versa. Thus, ev­idence is mounting that some patients with ocular myasthenia may have a disease that is not only milder but distinctive from the form that may be­gin with eye signs, but which evolves into a gen­eralized form. This may explain why a high pro­portion of exclusively ocular myasthenics have no detectable acetylcholine receptor antibodies. Other differences that characterize exclusive ocular my­asthenics are as follows: 1. Higher incidence of elderly and male patients 2. Less pronounced and different HLA associa­tions 3. No association with autoimmune disease or with thymoma 4. Poorer response to acetylcholine esterase in­hibitors and thymectomy 5. Better response to steroids To these characteristics we now add autoantibod­ies with different specificities ( 49). Another series of experiments undertaken to un­derstand this same question are reviewed by Otta ( 50). He and his coworkers have found certain pat­terns of motor innervation in human extraocular muscle that are not found in limb muscles. Epitopes that are unique to extraocular muscle endplates exist, and some ocular myasthenics have antibodies that are specifically targeted to these epitopes. By passive transfer it was determined that these antibodies are functionally active and can cause acetylcholine receptor loss in eye muscle endplates. Another difference between extraocular muscle and skeletal muscle is the presence of an embryonic gamma subunit in extraocular muscle mitochondrial RNA ( mtRNA), which is absent in skeletal muscle ( 51). Myasthenia patients fre­quently have antibodies and T- helper cells specific for embryonic acetylcholine receptors. The fact that adult extraocular muscle continues to express this protein may then help explain why ocular muscles are so frequently involved preferentially ( 51). Dysthyroid Ophthalmopathy A study of 15 patients with dysthyroid ophthal­mopathy attempts to clarify the relationship be­tween orbitopathy and such clinical manifestations as retraction or swelling of the upper eyelid and disturbance of vertical movement using sagittal magnetic resonance imaging ( 52). The authors found that the levator paplebrae was enlarged in all eyes with upper eyelid retraction. In almost 90% of eyes with apparent lid swelling there was enlargement of the preaponeurotic fat or submus- / Neuro- Ophthaltnol, Vol. 14, No. 4, 1994 230 B. SKARF cular fat pad. All eyes that had a disturbance of infraduction had lost the " clear space" between the superior rectus and levator palpebral muscle seen in control eyes. The inferior rectus muscle was enlarged in 80% of eyes with a disturbance in supraduction. On the whole, the correlation be­tween MRI abnormalities and clinical findings was quite high. A number of immunohistochemical studies on cultured eye muscle ( myoblasts) have been de­signed to elucidate the special susceptibility of these muscles in patients with thyroid disease ( 53- 55). Differences in the reactivity of patient versus control sera were shown in the binding character­istics of eye muscle preparations and in their met­abolic activation and creatine kinase activity ( 53). Another study compared the immunohistology of eye muscle in patients who had stabilized, quies­cent orbital pseudotumor and dysthyroid ophthal­mopathy ( 54). Both groups of patients showed higher expression of HLA- DR, while elevated ex­pression of HLA class- I antigens and C3 was ob­served only in the muscle taken from patients with orbital pseudotumor. The authors conclude that the presence of these antigens may indicate that the inflammatory disease may still be active in pa­tients who are in apparent remission ( 54). A review of autoantigens in dysthyroid ophthal­mopathy ( 55) highlights the prevalence of corre­sponding autoantibodies. One of these autoanti­bodies ( aD), is expressed in eye muscle and thy­roid, but not in skeletal muscle, and therefore may be important in the pathogenesis of dysthyroid ophthalmopathy. The authors speculate that the existence of additional proteins shared by thyroid and eye muscle, which are the targets of serum antibodies and/ or of blood or thyroidal T lympho­cytes, would support the notion that immunologic cross- reactivity is the best explanation for the as­sociation of orbital and thyroid autoimmunity. There is a high prevalence of antibodies to most the autoantigens discovered ( 55). A retrospective review of 21 patients with dys­thyroid ophthalmopathy treated with super volt­age radiation therapy to the orbits and six compa­rable patients who had not undergone radiother­apy fails to disclose any significant differences in muscle size on CT or in proptosis, visual acuity, or intraocular pressure rise on upgaze at one year fol­low- up ( 56). The forementioned soft- tissue signs improved in both groups. The authors suggest that radiation therapy " may shorten or blunt the acute active phase of the disease" and that " the benefits of orbital radiation therapy should be seen, at best, as an improvement of soft- tissue signs, not long-term change in radiologic parameters of muscle size" ( 56). Chronic Progressive External Ophthalmoplegia Cytochrome oxidase is the terminal enzyme of the respiratory chain catalyzing the reduction of molecular oxygen to water in mitochondria. Ab­normalities of this enzyme are associated with many human mitochondrial disorders, including chronic progressive external ophthalmoplegia. A microphotometric enzyme assay of cytochrome ox­idase, which allows for the measurement of en­zyme activity in individual muscle fibers, was used to study abnormalities of cytochrome- c oxidase in 12 patients with Kearn- Sayre syndrome, chronic progressive external ophthalmoplegia, or Leigh's syndrome ( 57). Patients with chronic progressive external ophthalmoplegia and Kearn- Sayre syn­drome showed abnormal heterogeneity of cy­tochrome c oxidase activity. It was felt that the extreme variability in enzyme activity was an indi­cator of a probable abnormality in mitochondrial DNA ( mtDNA). Indeed, most of the patients with chronic progressive external ophthalmoplegia had deletions or duplications of their mtDNA. Further­more, it was felt that a homogeneous distribution of cytochrome c oxidase defects in muscle fibers, such as was noted in Leigh's syndrome, would most likely be associated with defects of the nu­clear genome. There is a loss of respiratory chain function with aging, and this has been linked to decreased cy­tochrome c oxidase activity in muscle fibers, in­cluding those in extraocular muscle. A study de­signed to determine whether this deficiency is due to lack of mitochondrial- or nuclear- coded subunits of the enzyme examined the mtDNA from extraoc­ular muscles of humans over age 70 ( 58). The re­sults suggest that there are different molecular al­terations of mtDNA, and these probably do not contribute substantially to the decrease in cy­tochrome c oxidase activity with increasing age. The authors attribute this decreased capacity to nuclear factors. Miscellaneous Diseases of Eye Muscle Involvement of the extraocular muscles with sar­coidosis is rare. A 15- year- old boy presented with bilateral painful ophthalmoplegia, diplopia, and enlargement of the extraocular muscles ( 59). Bi­opsy demonstrated granulomatous infiltration of the muscle with sarcoidosis. / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 ANNUAL REVIEW- EYE MOVEMENTS 231 A 66- year- old man who presented with ptosis, proptosis, and decreased motility of one eye was found to have a metastatic renal cell carcinoma to his orbit ( 60). There was bone destruction and in­tracranial extension of the tumor mass. The pri­mary mass in his kidney was only discovered sec­ondarily, making this a most unusual presentation for this type of tumor. A 22- year- old patient who developed diplopia with limitation of vertical movements in her right eye was found to have metastatic alveolar rhabdo­myosarcoma to the orbit ( 61). The patient had a known primary paravaginal lesion with metaste-ses, diagnosed 26 months earlier and treated with chemotherapy, local radiotherapy, and an autolo­gous untreated bone marrow transplant. A child developed spontaneous episodic con­tractions of the left lateral rectus muscle 16 months after an anaplastic astrocytoma of his thalamus was irradiated ( 62). These involuntary contractions were triggered by extreme gaze in the direction of the affected lateral rectus muscle and are attributed to ocular neuromytonia of the abducens nerve caused by radiation injury. The phenomena per­sisted for 22 months before disappearing. A 6- year follow- up study of eye movements in six patients with myotonic dystrophy was con­ducted to help elucidate the pathophysiologic mechanism of this disease ( 63). The authors found no significant differences in the latency of visually guided saccades or in the mean gain of smooth pursuits over the 6 years. The study did demon­strate a progressive decrease in Vmax of horizontal saccades, which correlated with progression of limb weakness ( Mathieu score). Since Vmax reflects myopathic changes, the authors feel their data support progressive involvement of extraocular muscles in this disease, and they conclude that this is most consistent with a peripheral ( myopathic) pathophysiologic mechanism ( 63). A patient with congenital muscular dystrophy ( non- Fukuyama type) had slow saccades, presum­ably due to muscle weakness, as well as corneal opacities. The patient had prominent muscular wasting and weakness, predominantly in the prox­imal limbs ( 64). The histopathology of extraocular muscles ob­tained during enucleation procedures on diabetics over 50 years of age were compared to muscle sam­ples from elderly patients who did not have dia­betes ( 65). Patients with diabetes had degenerative and atrophic changes which affected all compo­nents of the musculature, that is, the muscle tissue itself, the vessels, connective tissue, nerves and nerve endings, and mitochondria. The authors at­tribute the atrophic and degenerative alterations to the primary vasculopathy they have noted. A review of ocular motility disturbances which can result from sinus surgery, including descrip­tions of six new cases ( 66), found that the medial rectus was the muscle most commonly injured. However, the superior oblique, medial rectus and inferior rectus could be affected, depending on the surgical approach. The article reviews the various types of injuries and their etiologies and provides guidelines for their management, emphasizing ap­propriately timed intervention. Medial rectus inju­ries had the poorest recovery rate, with or without intervention. In a review of nine patients who developed a paresis of a vertical rectus muscle following cata­ract surgery, the authors determined that there was no correlation with surgical technique but con­cluded that peribulbar, or atypical retrobulbar an­esthesia produced permanent paresis of the af­fected muscles by a myotoxic effect of the local anesthetic ( 67). The authors argue that the large quantity of anesthetic used in these cases bathed the affected muscle causing muscle fiber destruc­tion, thus compromising function. Appropriate measures to avoid this complication are proposed. Methodology Although sophisticated electro- optical and mag­netic- search coil eye trackers have become the ac­cepted standard in eye movement research, tradi­tional electro- oculography is still widely used. The intertest reliability of quantitative analysis of sac­cadic and smooth pursuit eye movement as mea­sured by electro- oculography was examined ( 68). The coefficients of reliability ( R) of a series of rela­tionships derived from basic measurements col­lected before and after a 1- week interval were found to be good to excellent ( R values between 63 and 91). Visual evoked potentials have been used to monitor optic nerve function during neurosurgical procedures. In a variation of this approach, evoked extraocular muscle activity can be recorded intra-operatively to monitor ocular motor nerve function during surgery, much the same way facial nerve function is monitored during excision of acoustic neuromas ( 69). Compound muscle action poten­tials can be monitored directly from the extraocular muscles, while the ocular motor nerves are elec­trically stimulated intracranially. The authors claim that the nerve stimulation techniques provide surgeons with additional information during sur­gery, which can help improve operative outcome. / Neuro- Ophthalmol, Vol. 14, No. 4, 1994 232 B. SKARF REFERENCES 1. 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