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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA SYNOPSIS OF DISSERTATION “CLINICAL STUDY, ETIOPATHOGENESIS AND MANAGEMENT OF OCULOMOTOR NERVE PALSY” Submitted by Dr. PRANITHA PRABHU. M.B.B.S. POST GRADUATE DEGREE STUDENT IN OPHTHALMOLOGY (M.S.) Under the guidance of Prof .Dr. PADMINI, H.R, M.B.B.S., M.S.,D.O.M.S DEPARTMENT OF OPHTHALMOLOGY A.I.M.S, B.G.NAGARA-571448. DEPARTMENT OF OPHTHALMOLOGY ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA-571448 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION Dr. PRANITHA PRABHU. # 18, KALPATHARU BHAVANA, P.G. HOSTEL, A.I.M.S., B.G.NAGARA. NAGAMANGALA TALUK, MANDYA DISTRICT-571448 KARNATAKA. 1 NAME OF THE CANDIDATE AND ADDRESS (in block letters) 2. NAME OF THE INSTITUTION ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA. 3. COURSE OF STUDY AND SUBJECT M.S. IN OPHTHALMOLOGY 4. DATE OF ADMISSION TO COURSE 5. TITLE OF THE TOPIC 08-07-2013 A CLINICAL STUDY,ETIOPATHOGENESIS AND MANAGEMENT OF OCULOMOTOR NERVE PALSY” . BRIEF RESUME OF INTENDED WORK 6. 7 APPENDIX-I 6.1 NEED FOR THE STUDY APPENDIX-IA 6.2 REVIEW OF LITERATURE APPENDIX-IB 6.3 OBJECTIVES OF THE STUDY APPENDIX-IC MATERIALS AND METHODS APPENDIX-II 7.1 SOURCE OF DATA APPENDIX-IIA 7.2 METHOD OF COLLECTION OF DATA : (INCLUDING SAMPLING PROCEDURE IF ANY) APPENDIX-IIB 7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS, IF SO PLEASE DESCRIBE BRIEFLY. APPENDIX-IIC 7.4 HAS ETHICAL CLEARENCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3 8. YES APPENDIX-IID APPENDIX – III LIST OF REFERENCES 1 9. SIGNATURE OF THE CANDIDATE 10. REMARKS OF THE GUIDE 11 NAME AND DESIGNATION (in Block Letters) Isolated oculomotor nerve palsy cases do come to our department next in order to abducent nerve palsy. Hence this study may be of clinical significance since the modalities of diagnostic techniques are available in this institution. Hence I recommend this study for submission. 11.1 GUIDE Dr. PADMINI,H.R., M.B.B.S., M.S., D.O.M.S., PROFESSOR AND HEAD DEPARTMENT OF OPHTHALMOLOGY AIMS, B.G. NAGARA-571448 11.2 SIGNATURE OF THE GUIDE - 11.3 CO-GUIDE (IF ANY) 11.4 SIGNATURE Dr. PADMINI,H.R., M.B.B.S., M.S., D.O.M.S., PROFESSOR AND HEAD DEPARTMENT OF OPHTHALMOLOGY, AIMS, B.G. NAGARA-571448 11.5 HEAD OF DEPARTMENT 11.6 SIGNATURE 2 12 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL The facilities required for the investigation will be made available by the college Dr. M.G SHIVARAMU MBBS, MD PRINCIPAL, AIMS, B.G. NAGARA. 12.2 SIGNATURE 3 APPENDIX-I 6. BRIEF RESUME OF THE INTENDED WORK: APPENDIX-IA 6.1 NEED FOR THE STUDY: A perfect alignment between the motor system of two eyes is responsible for viewing an object as single. The extraocular muscles of both eyes work in coordination. When any one or more of these falter, it may manifest as double vision , deviation of eyes or sometimes with pain. Patients may sometimes present to the ophthalmologist for one of these complaints ,may be referred by another physician or be seen accidentally while they just come for a routine checkup. This may be one of the first manifestation of a serious emergency like a posterior communicating artery aneurysm or a multisystem disease like diabetes. So every case has to be evaluated and its probable etiology identified. Here lies the role of an ophthalmologist to decide whether follow up and observation will suffice or may require emergency intervention by a neurosurgeon. The diagnosis and management of third nerve dysfunction vary according to the age of the patient, the characteristics of the third nerve palsy, and the presence of associated symptoms and signs. Third nerve palsies can result from lesions located anywhere from the oculomotor nucleus to the termination of the third nerve in the extraocular muscles within the orbit, and may be the herald manifestation of underlying neurological emergencies such as intracranial aneurysm, pituitary apoplexy, and giant cell arteritis. Recent advances in noninvasive neuroimaging facilitate early diagnosis, but the management of a patient presenting with isolated third nerve palsy remains a challenge. 4 APPENDIX-IB 6.2 REVIEW OF LITERATURE Isolated third nerve palsies in patients over age 50 most commonly result from microvascular ischemic demyelination in patients with vasculopathic risk factors including diabetes, hypertension, hyperlipidemia and advanced age. Cranial mononeuropathies have been recognized for centuries. Until the early and middle part of the twentieth century, most palsies were thought to arise as a result of tumors, trauma, infections or nutritional deficiencies. Syphilis, tuberculosis and vitamin deficiencies were felt to be important causes. The first important pathologic papers on this topic were written by Dreyfus et al 1, and Asbury, et al2,3. The Asbury paper2, details the histopathology of an 88 year old woman with diabetes that had a recovered third nerve palsy on one side and died while about 1 month after developing a pupil sparing third nerve palsy on the other. Their findings were highlighted by a non inflammatory, presumably ischemic, demyelinating focus in the intracavernous portion of the third nerve on the acutely involved side. No evidence of any axonal damage in either the acutely involved or recovered nerve was found nor was any occlusion of any of the large blood vessels off of the posterior cerebral, posterior communicating or intracavernous carotid arteries. However, there was widespread thickening and hyalinization of arteriolar and capillary walls with luminal narrowing of the vasonervorum (50-80u diameter vessels). These changes were most extensive in the intracavernous portion of both third nerves and to a lesser extent in the subararchnoid sections and uncommon elsewhere in the body. They concluded that ischemia was the mechanism of the dysfunction based on the focal nature of the lesion, its bland non inflammatory character, the blood vessel changes described above and the clinical pattern of recovery. However, they did not 5 discover what precipitated the ischemic event. In attempting to explain the commonly associated pain, they did not find involvement of the intracavernous trunks of the trigeminal nerve but they posited that perhaps there were pain sensitive nerve endings within the sheath and endoneurium itself. They noted relative sparing of the most peripheral parts of the nerve where the smaller (presumably) pupillary fibers were located. In adults, the most common cause of acute ocular motor mononeuropathies is microvascular ischemia4,5. It is worth noting that the microvascular nature of this ischemia remains a presumptive diagnosis based on very limited histopathologic data and presumed because of the absence of other associated neurologic symptoms or signs, no new findings in the follow up period, a chronic stable course associated with spontaneous recovery and the setting in which these palsies generally occur, namely older adults with vasculopathic risk factors, most notably diabetes but also hypertension, hyperlipidemia and simply advancing age6-8 . In all of the large series that have found “ischemia” as the most common cause of the ocular motor nerve palsy, the diagnosis was presumptive and not based on negative high quality imaging. In the past era when the pathogenesis and benign nature of the ischemic cranial nerve palsies were first recognized, only very primitive and invasive tests were available to diagnose vascular lesions and brain tumors and in vivo demonstration of brainstem stroke was impossible. The ischemic third nerve palsy can arise in the setting of diabetes, hypertension, hyperlipidemia and advanced age.7,9 Pain is a common feature and can be quite severe especially in the young vasculopathy making it an unreliable method of distinguishing ischemic palsies from more ominous causes. However isolated third nerve palsies10-20 can arise in many different circumstances. Midbrain strokes and hemorrhages have been reported to cause isolated pupil involving or pupil sparing third nerve palsies. Isolated and relative pupil sparing third nerve palsies have also been described in patients with meningioma, 6 metastases, neurocysticercosis, and severe internal carotid artery stenosis. As well even divisional palsies have been reported as manifestations of midbrain stroke or mass lesions.16 The assumption that these alternative diagnoses must be very rare may be faulty if neuroimaging has only been rarely ordered in these patients. Other vascular lesions such as posteriorly draining dural fistulas , and cavernous sinus aneurysms can cause isolated third nerve palsies. Third nerve palsy is also the most common motility deficit in patients with pituitary apoplexy and it may be isolated and present with a great degree of variability in the severity of pain and headache. Lastly, third nerve palsies are well recognized to arise in the setting of vasculitis, particularly temporal arteritis, and after minor trauma in patients harboring a mass lesion. In 1967, Zorilla and Kozak reported pupil sparing in 16 of 20 patients with oculomotor palsy in association with diabetes mellitus. When the astute physician could recognize the pupil sparing feature of a third nerve palsy and pronounce that this was unlikely to be a compressive or vascular lesion, a patient could be spared an invasive test such as an angiogram or pneumoencephelogram. More recently, it is well recognized that vasculopathic palsies frequently involve the pupil to some extent, and as well that, in some patients, diabetic changes affect the iris sphincter and that pupillary efferent function maybe abnormal in patients who have had pan retinal photocoagulation. These exam features can limit the clinician’s ability to use the pupil exam to exclude aneurysms. With this in mind, the most “high stakes” situations would include third nerve palsy presenting with pupillary involvement, only relative pupil sparing or younger patients in whom the pupil exam can not be relied upon in a patient that maybe harboring an aneurysm. In addition, although rare, relative or complete pupil sparing has been reported in patients with aneurysms especially early in the clinical course. 7 Causes of Oculomotor Palsy: Oculomotor palsy can arise as a result of a number of different conditions. A. Congenital Oculomotor Palsy The origins of the vast majority of congenital oculomotor palsies are unknown, or idiopathic to use the medical term. There is some evidence of a familial tendency to the condition, particularly to a partial palsy involving the superior division of the nerve with an autosomal recessive inheritance. The condition can also result from aplasia or hypoplasia of one or more of the muscles supplied by the oculomotor nerve. It can also occur as a consequence of severe birth trauma. B. Acquired Oculomotor Palsy 1. Vascular disorders such as diabetes, heart disease, atherosclerosis and aneurysm, particularly of the posterior communicating artery 2. Space occupying lesions or tumours, both malignant and non-malignant 3. Inflammation and Infection 4. Trauma 5. Demyelinating disease (Multiple sclerosis) 6. Autoimmune disorders such as Myasthenia gravis 7. Post operatively as a complication of neurosurgery 8. Cavernous sinus thrombosis 8 Pathophysiology: The anatomical relationship of the various portions of the third cranial nerve accounts for many of the clinical features of third cranial nerve palsy as outlined below. Nuclear portion: The cell bodies for axons that travel in the oculomotor nerve reside in the column-shaped nuclear groups on either side of the midbrain tegmentum. The axons destined for each extraocular and intraocular muscle derive from a specific subnucleus. Fascicular intraparenchymal midbrain portion: The fascicular portion of the oculomotor nerve courses ventrally from the nucleus in the dorsal midbrain tegmentum, passes through the red nucleus, and emerges from the medial aspect of the cerebral peduncle. Fascicular subarachnoid portion: The cisternal portion of the nerve is in the subarachnoid space anterior to the midbrain and in close proximity to the posterior communicating artery. Berry aneurysm at the junction between the posterior communicating artery and the internal carotid artery is an important cause of oculomotor nerve palsy. Fascicular cavernous sinus portion: The next segment of the oculomotor nerve runs through the lateral wall of the cavernous sinus superiorly. It enters the cavernous sinus just above the petroclinoid ligament and inferior to the interclinoid ligament. Masses invading the cavernous sinus from within the sella are most likely to cause third cranial nerve dysfunction prior to involvement of the other cranial nerves in the cavernous sinus. This is probably because of the oculomotor nerve's close proximity to the unyielding interclinoid ligament above and the petroclinoid ligament below. 9 Fascicular orbital portion: The oculomotor nerve enters the orbit through the superior orbital fissure adjacent to the fourth cranial nerve. The nerve branches into superior and inferior divisions, usually within the posterior orbit, but, occasionally, the branching occurs as far back as the cavernous sinus segment. The superior division innervates the levator palpebrae and the superior rectus muscles; the inferior division innervates all the other muscles, including the iris sphincter, which constricts the pupil. The axons for most of the muscles are uncrossed from the nucleus to the eye, but there are 2 exceptions: (1) Axons for the levator palpebrae come from both sides of the central caudal subnucleus via crossed and uncrossed pathways. (2) Those for the superior rectus muscle come from the superior rectus subnucleus on the contralateral side. The pupillomotor and ciliary muscle neurons derive from the EdingerWestphal subnucleus, which is in the midline in the most rostral and anterior part of the oculomotor nerve nucleus. These autonomic pathways are all ipsilateral or uncrossed. The oculomotor nerve innervates the following extraocular muscles of either eye: superior rectus, inferior rectus, medial rectus, inferior oblique, levator palpebrae, ciliary muscle, and iris sphincter. Third nerve palsy results from damage to the oculomotor nerve anywhere in its course from the nucleus in the dorsal mesencephalon, its fascicles in the brainstem parenchyma, the nerve root in subarachnoid space, or in the cavernous sinus or posterior orbit. Damage to the third nerve nucleus results in an ipsilateral third nerve palsy with contralateral superior rectus under action and bilateral ptosis. Damage to the third nerve fascicles results in an ipsilateral third nerve palsy with contralateral hemiparesis (Weber's syndrome), contralateral intention 10 tremor (Benedikt's syndrome), or ipsilateral cerebellar ataxia (Nothnagel's syndrome). Vascular infarct, metastatic disease and demyelinization are the common causes of brainstem involvement. Damage to the third nerve within the subarachnoid space produces an isolated third nerve palsy. The main causes are compression of the nerve by an expanding aneurysm of the posterior communicating artery or the basilar artery, and ischemic vasculopathy. There will always be pain in aneurysmal compression and pupillary involvement is typical, though there have been infrequent cases of aneurysmal compression that did not initially affect pupillary function. In ischemic vascular nerve third palsies, pain is frequent and the pupil is typically normal and reactive. Damage to the third nerve in the cavernous sinus, superior orbital fissure, or posterior orbit is unlikely to present as third nerve palsy due to the confluence of other structures in these areas. Cavernous sinus involvement may also include pareses of cranial nerves IV, VI and V1, and an ipsilateral Horner's syndrome. The most common causes of damage in these areas include metastatic disease, inflammation, herpes zoster, carotid artery aneurysm, pituitary adenoma and apoplexy, and sphenoid wing meningioma. Features of Oculomotor Palsy: The features of third nerve palsy are: It may be complete or incomplete and it may be congenital or acquired. 1. Ptosis - due to paralysis of Levator Palprebrae Superioris 11 2. Deviation - eyeball is turned down , out and slightly intorted due to unopposed action of the lateral rectus and the superior oblique 3. Ocular movements – restriction of the following movements: i. adduction - due to paralysis of medial rectus, ii. elevation - due to paralysis of superior rectus and inferior oblique, iii. depression - due to paralysis of inferior rectus and iv. extorsion - due to paralysis of inferior rectus and inferior oblique. 4. Pupil - is fixed and dilated due to paralysis of sphincter pupillae 5. Accomodation - completely lost due to paralysis of ciliary muscle 6. Crossed diplopia - appears on manually raising the eyelid, which occurs due to paralytic divergent squint 7. Head posture - if the pupillary area is uncovered the head takes a posture consistent with the directions of actions of paralysed muscle i.e head is turned to the opposite side , tilted towards the same side and chin is slightly raised. 12 APPENDIX-IC 6.3 AIM OF THE STUDY To analyse the various etiologies and pathogenic factors leading to oculomotor nerve paralysis. To analyse the common clinical patterns arising in the background of acquired oculomotor nerve palsy . 6.4 OBJECTIVES OF THE STUDY To assess the visual outcome in patients with isolated third nerve palsy. To assess the binocular alignment in patients with isolated third nerve palsy. 13 APPENDIX-II 7.0 MATERIALS AND METHODS APPENDIX-II A 7.1 SOURCE OF DATA The material for the present study is proposed to be collected from the patients presenting themselves directly to Department of Ophthalmology (Hospital: Adichunchanagiri Institute of Medical Sciences, B.G.Nagara, Mandya district) or referred by Physician will be undertaken for the study. A prospective cohort study of a sample size of a minimum of 20 patients fulfilling the mentioned inclusion criteria will be a part of this study. APPENDIX-II B 7.2 METHOD OF COLLECTION OF DATA Those patients on routine screening having isolated oculomotor nerve palsy have been selected for this study. Inclusion criteria: Both male and female patients. Isolated oculomotor nerve palsy. Exclusion criteria: Congenital oculomotar nerve palsies have been excluded. Patients with incomitant squint due to myogenic, myasthenic and restrictive causes have been excluded. 14 APPENDIX-II C 7.3 Does the study require any investigation or intervention to be conducted on the patients, if so please describe briefly. Yes it requires the following investigations to be conducted on patients included in this study. Patients with paralytic squint were identified and details regarding their name, age, sex, symptoms, and its duration and any change in the symptoms between their presentation and their onset have been recorded. Detailed history regarding the incidences that preceded the onset of symptoms like trauma [trivial or severe], headache fainting attacks, numbness, etc., was taken. Past history of any previous episodes of similar nature and the treatment given for the same has been noted. History of systemic illnesses like hypertension, diabetes-mellitus, thyroid abnormalities, and seizure disorder and previous neurological involvement in any other disorders like tuberculosis, syphilis, were noted. History specific to ocular complaints such as double vision, blurring of vision, field defects, and vestibular complaints like vertigo, tinnitus, ear discharge, and bleeding per year have been recorded. Personal history regarding smoking, alcohol intake and diet pattern were asked and recorded. A complete haemogram, urine analysis for albumin, sugar, and deposits, blood sugar VDRL, Mantoux test, X-ray of skull (both anteroposterior and lateral)and paranasal sinuses and optic foramen has been done for all patients. CT-scan was done in almost all trauma cases and in other cases whenever possible. MRI-scan was done whenever it was possible. Certain special tests like neostigmine test has been done in certain cases to diagnose and to differentiate myasthenia gravis from nerve palsies. 15 Follow up of these cases has been done at the end of 4 weeks, 8weeks, 12weeks, and 6 months in case of patients living nearby and at an interval of 4weeks, 12weeks, and 6months in case of patients coming from far off places. OPTHALMOLOGICAL EXAMINATION: General: Systemic (CNS): Higher Function Cranial Nerves Sensory and Motor Reflex Cerebellar Systems Ocular: Head Posture Facial Asymmetry Lid Position Extra Ocular Movements Anterior Segment Pupil Visual acuity Fundus Investigations General: Pulse BP Temperature Ocular: 16 Visual acuity Refraction Intra-ocular Pressure Hess charting Diplopia Charting Fields Orthoptic evaluation: Cover Test Prism Bar Cover Test Worth’s Four Dot Test Binocular Single Vision Lab Investigations: Haemogram RBS Urine Routine Mantoux, VDRL X-Ray, CT Scan and MRI Scan Intervention: Medical management is watchful waiting, since nearly all patients undergo spontaneous remission of the palsy, usually within 6-8 weeks. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment of choice for the pain. When diplopia is from large-angle divergence of the visual axes, patching one eye is the only short-term solution. When the angle of deviation is smaller, fusion in primary position often can be achieved using horizontal or vertical prism or both. 17 Surgical management includes clipping, gluing, coiling, or wrapping of the berry aneurysm by a neurosurgeon in the acute stage. Patients who do not recover from third cranial nerve palsy after 6-12 months may become candidates for eye muscle resection or recession to treat persistent and stable-angle diplopia. Some of these patients also may require some form of lid-lift surgery for persistent ptosis that restricts vision or is cosmetically unacceptable to the patient. 18 APPENDIX-II D PROFORMA APPLICATION FOR ETHICS COMMITTEE APPROVAL SECTION-A a) Title of the Study “CLINICAL STUDY, ETIOPATHOGENESIS AND MANAGEMENT OF OCULOMOTOR NERVE PALSY” b) Principal Investigator (Name and Designation) Dr.PRANITHA PRABHU P.G.IN OPHTHALMOLOGY ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA MANDYA DISTRICT-571448 c) Co-investigator (Name and Designation) d) Name of the Collaborating Department/ Institutions e) Whether permission has been obtained from the Heads of the collaborating departments & Institution SECTION-B a) SUMMARY OF THE Project Prof.Dr.PADMINI, H.R., M.B.B.S., M.S., D.O.M.S. PROFESSOR & HEAD DEPARTMENT OF OPHTHALMOLOGY A.I.M.S., B.G.NAGARA-571448 DEPARTMENT OF MEDICAL EDUCATION YES APPENDIX-I SECTION-C a) Objectives of the Study APPENDIX-I C SECTION-D a) Methodology APPENDIX-II B A Where the proposed study will be undertaken ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA MANDYA DISTRICT-571448 B Duration of the Project 18 Months 19 C Nature of the subjects Does the study involve adult patients? YES Does the study involve Children? NO Does the study involve normal volunteers? NO Does the study involve Psychiatric patients? NO Does the study involve pregnant women? YES D If the study involves health volunteers i. Will they be institute students? NO ii. Will they be institute employees? NO iii. Will they be paid NO iv. If they are to be paid, how much per session? NA E Is the study a part of multi central trial? NO F If yes, who is the coordinator (Name and Designation NA Has the trial been approved by the Ethics Committee of the other centers? NA If the study involves the use of drugs, please indicate whether: NA i. The drug is marketed in India for the indication in which it will be used in the study ii. The drug is marketed in India but not for the indication in which it will be used in the study iii. The drug is only used for experimental use in human iv. Clearance of the drugs controller of India has been obtained for. G NA Use of the drug in healthy volunteers - Use of the drug in-patients for a new indication - Phase one and two clinical trials - Experimental use in-patients and healthy volunteers. - How do you propose to obtain the drug to be used in the study? NA Gift from a drug company - Hospital supplies - Patients will be asked to purchase - Other sources (explain) - 20 H Funding (If any) for the project please state NA None - Amount - Source - To whom payable - I Does any agency have a vested interest in the outcome of the Project? NO J Will data relating to subjects/controls be stored in a computer? YES K Will the data analysis be done by: L The researcher? YES The funding agent NO Will technical/nursing help be required from the staff of hospital NO If yes, will it interfere with their duties? - Will you recruit other staff for the duration of the study? - If Yes, give details of: - i. Designation ii. Qualification iii. Number iv. Duration of employment M N Will informed consent be taken? If yes, Will it be written informed consent NO Will it be oral consent? YES Will it be taken from the subject themselves? YES Will it be from the legal guardian? If no, give reason YES Describe design, Methodology and techniques APPENDIX-II Ethical clearance has been accorded Chairman PG Training-cum-Research Institute AIMS, B.G.Nagara 21 APPENDIX-III 8. LIST OF REFERENCES 1. Dreyfus PM, Hakim S, Adams RD. Diabetic ophthalmoplegia; report of case, with postmortem study and comments on vascular supply of human oculomotor nerve. AMA Arch Neurol Psychiatry 1957;77:337-349. 2. Asbury AK, Aldredge H, Hershberg R, et al. Oculomotor palsy in diabetes mellitus: a clinico-pathological study. Brain 1970;93:555-566. 3. Asbury AK, Fisher CM, Aldredge H, et al. Diabetic ophthalmoplegia: a clinico-pathologic investigation. Trans AmNeurol Assoc 1969;94:64-68. 4. Richards BW, Jones FR, Jr., Younge BR. Causes and prognosis in 4,278 cases of paralysis of the oculomotor, trochlear, and abducens cranial nerves. Am J Ophthalmol 1992;113:489-496. 5. Rush JA, Younge BR. Paralysis of cranial nerves III, IV, and VI. Cause and prognosis in 1,000 cases. Arch Ophthalmol 1981;99:76-79. 6. Sanders SK, Kawasaki A, Purvin VA. Long-term prognosis in patients with vasculopathic sixth nerve palsy. Am J Ophthalmol 2002;134:81-84. 7. Jacobson DM, McCanna TD, Layde PM. Risk factors for ischemic ocular motor nerve palsies. Arch Ophthalmol 1994;112:961-966. 8. Capo H, Warren F, Kupersmith MJ. Evolution of oculomotor nerve palsies. J Clin Neuroophthalmol 1992;12:21-25. 9. Teuscher AU, Meienberg O. Ischaemic oculomotor nerve palsy. Clinical features and vascular risk factors in 23 patients. J Neurol 1985;232:144-149. 10. Shintani S, Tsuruoka S, Minato Y, et al. Radiologic-clinical correlation. Isolated third nerve palsy caused by midbrain hemorrhage. AJNR Am J Neuroradiol 1994;15:1508-1511. 22 11. Rabadi MH, Beltmann MA. Midbrain infarction presenting isolated medial rectus nuclear palsy. Am J Med 2005;118:836-837. 12. Nadeau SE, Trobe JD. Pupil sparing in oculomotor palsy: a brief review. Ann Neurol 1983;13:143-148. 13. Mizushima H, Seki T. Midbrain hemorrhage presenting with oculomotor nerve palsy: case report. Surg Neurol 2002;58:417-420. 14. Kwon JH, Kwon SU, Ahn HS, et al. Isolated superior rectus palsy due to contralateral midbrain infarction. Arch Neurol 2003;60:1633-1635. 15. Kumar P, Ahmed I. Pupil-sparing oculomotor palsy due to midbrain infarction. Arch Neurol 1992;49:348. 16. Kim JS, Kang JK, Lee SA, et al. Isolated or predominant ocular motor nerve palsy as a manifestation of brain stem stroke. Stroke 1993;24:581-586. 17. Hopf HC, Gutmann L. Diabetic 3rd nerve palsy: evidence for a mesencephalic lesion. Neurology 1990;40:1041-1045. 18. Fujioka T, Segawa F, Ogawa K, et al. Ischemic and hemorrhagic brain stem lesions mimicking diabetic ophthalmoplegia. Clin Neurol Neurosurg 1995;97:167-171. 19. Champion BL, Choy F, Schrieber L, et al. Isolated fascicular oculomotor nerve palsy as the initial presentation of the antiphospholipid syndrome. J Clin Neurosci 2002;9:691-694. 20. Breen LA, Hopf HC, Farris BK, et al. Pupil-sparing oculomotor nerve palsy due to midbrain infarction. Arch Neurol 1991;48:105-106. 23