The Work Up of Isolated Ocular Motor Palsy: Who to Scan and Why

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1 The Work Up of Isolated Ocular Motor Palsy: Who to Scan and Why Nicholas Volpe, MD Scheie Eye Institute, University of Pennsylvania Philadelphia, Pennsylvania LEARNING OBJECTIVES 1. To identify common causes of isolated cranial nerve palsies. 2. To be familiar with the available literature concerning the management and work up of patients with isolated cranial nerve palsies. 3. To be familiar with management choices and strategies of other neuro ophthalmologists seeing similar patients. CME QUESTIONS 1. Other frequently identified causes of isolated cranial nerve palsies include? 2. What vessels have been shown to be involved in the pathogenesis of ischemic cranial mononeuropathies? 3. When studied prospectively, the rate at which relevant and important findings are found on magnetic resonance imaging in patients over 50 years of age with isolated ocular motor palsies is? KEY WORDS 1. cranial nerve palsy 2. third nerve palsy 3. fourth nerve palsy 4. sixth nerve palsy 5. magnetic resonance imaging INTRODUCTION Isolated cranial mononeuropathies 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. Most patients will have negative imaging studies however with increasing quality of magnetic resonance imaging (MRI) patients with third, fourth and sixth nerve palsy are often found to have alternative causes of their palsy including brain stem strokes and hemorrhages, tumors, demyelination and pituitary apoplexy. The we know better attitude may not hold up based on prospective data that suggests that approximately 10% of these patients have important and related causes for these palsies that can be identified on MRI scan. Arguments not to image include pre test probability, low yield, the opportunity to work these patients up when they fail to recover and socioeconomic issues related to over utilization of neuroimaging. In addition to a significant prevalence of important diagnoses arguments for imaging include the chance of error by non experts, the chance of identifying important clues to the pathogenesis of ischemic cranial mononeuropathies and medical legal implications of delayed diagnoses. Ultimately the decision is based on each physician s individual experience and the patient s willingness to undergo testing or accept the risk of missed or delayed diagnoses. HISTORICAL PERSPECTIVE Isolated 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. Most early textbooks discussing the neuro ophthalmology of eye movements include only passing reference to diabetes as a cause. The first important pathologic papers on this topic were written by Dreyfus et al 1, and Asbury, et al 2,3. The Asbury paper 2, 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 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 2009 Annual Meeting Syllabus 99

2 endoneurium itself. They noted relative sparing of the most peripheral parts of the nerve where the smaller (presumably) pupillary fibers were located. OCULAR MOTOR NERVE PALSIES In adults, the most common cause of acute ocular motor mononeuropathies is microvascular ischemia 4,5. 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 age 6-8. 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. THIRD NERVE PALSIES The liveliest discussions about the work-up of patients with isolated cranial nerve palsies centers around third nerve palsies. The stakes are high and we believe that clinically, complete pupil sparing, is our safety net, helping to exclude the possibility of a compressive, vascular lesion. The entire controversy or hot topic nature of the decision to do imaging studies, has grown up around this clinical distinction and has extended itself to sixth and fourth nerve palsies for which the stakes are generally much lower. 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 vasculopath making it an unreliable method of distinguishing ischemic palsies from more ominous causes. However isolated third nerve palsies 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, 23 metastases, 24 neurocysticercosis, 26 and severe internal carotid artery stenosis. 27 As well even divisional palsies have been reported as manifestations of midbrain stroke or mass lesions. 16,25,26,28 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 29, 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 37. In 1967, Zorilla and Kozak reported pupil sparing in 16 of 20 patients with oculomotor palsy in association with diabetes mellitus 38. 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, 39,40 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. 41,42 Much has been written about the importance of the pupil and the relative degree of internal and external ophthalmoplegia in dictating the work up of patients with third nerve palsy This topic will be discussed in detail later in the symposium. SIXTH NERVE PALSY Sixth nerve palsies as well have been recognized to be common consequences of diabetes or other vasculopathy with a presumed ischemic etiology. Sixth nerve palsies have also been recognized for more than 100 years to be false, non-localizing signs of either elevated intracranial pressure or tumors not immediately in contact with the sixth nerve. At the same time, there is a wealth of literature that describes isolated sixth nerve palsies as manifestations of important intracranial disease. Like third nerve palsy, pontine, intraaxial strokes have been reported to cause isolated sixth nerve palsy in patients with diabetes and hypertension In patients under age 50 with sixth nerve palsies there is high prevalence of tumors and multiple sclerosis although many will turn out to be idiopathic. 53,54 Skull base neoplasms, especially meningiomas, 55,56 chordomas, 57 nasopharyngiomas, plasmacytomas, 62 and metastases (prostate, breast, lung) are common causes of sixth nerve palsy. Important vascular causes of sixth nerve palsy include dural cavernous sinus fistulas and intracavernous aneurysms. 63 Although resolution of the sixth nerve palsy is generally considered evidence of a vasculopathic palsy and a clinical 100 North American Neuro-Ophthalmology Society

3 feature that makes neuroimaging unnecessary, spontaneous recovery of sixth nerve palsies has been reported in patients harboring space occupying lesions. 64 FOURTH NERVE PALSY The common causes of isolated fourth nerve palsies include congenital, traumatic, and vasculopathic etiologies. Patients with congenital and traumatic etiologies are generally easy to recognize based on the clinical history (trauma) or the examination (congenital, inferior oblique overaction, large fusional amplitudes, head tilt). Truly isolated fourth nerve palsies in older individuals are almost always vasculopathic in etiology, although again isolated palsies have been reported as manifestations of midbrain hemorrhages, 65 pituitary macroadenoma, 66 posterior fossa tumors, 67,68 dural fistuals, 69 and schwanomas 70,71 and cavernomas of the fourth nerve. 72,73 Care must also be taken however in securing the diagnosis because of other important entities in the differential diagnosis of acquired hypertropias including thyroid eye disease, myasthenia gravis, and skew deviation. These represent distinct diagnoses each of which requires a different work up and management strategy. PROSPECTIVE DATA Because of the increasing frequency with which magnetic resonance imaging has successfully identified other causes for acute ocular motor mononeuropathies, we set out to try and answer this question in a prospective fashion, performing MRI scanning on a consecutive group of 66 patients, age 50 years and older with acute ocular motor mononeuropathies. This study reported by Chou etal., 39 was done because our own anecdotal experience was significant. Each of us had encountered important potentially treatable disorders including intraaxial and extraaxial neoplasms, demyelinating illness, brainstem infarcts and pituitary apoplexy in patients with seemingly isolated cranial nerve palsies (in the vasculopathic age group). These cases, of course, were noted and reported by others as well. Prior to this report, several retrospective analyses had indicated that the majority of patients with isolated cranial nerve palsies had a microvascular etiology and that work-up should be delayed in and effort to save costs by following patients and determining if work-up was needed only if they failed to recover. In this study all patients had isolated cranial nerve palsies with no other symptom besides headache or pain. All patients were seen and worked up within a month of their presentation and no patients had had previous neurosurgical procedures, lumbar punctures, head injuries or known diseases potentially associated with cranial nerve palsies such as infections or neoplasms. Those patients in whom a congenital etiology was suspected were also excluded. We did not identify demographic information or historical features including the quality of the pain or the temporal aspects of the evolution of the double vision as helpful in identifying those patients with alternative diagnoses. (Table 1) We identified 9 patients out of 66 that had what was judged to be important and TABLE 1. CHARACTERISTICS OF PATIENTS WITH ACUTE OCULAR MOTOR MONONEUROPATHIES OF PERIPHERAL MICROVASCULAR VS. OTHER ETIOLOGY Annual Meeting Syllabus 101

4 significant causes for their cranial nerve palsy. (Table 2) This included four patients with third nerve palsies, two of which were pupil sparing, four patients with sixth nerve palsies and only one patient with fourth nerve palsy. TABLE 2. ETIOLOGIES OTHER THAN PERIPHERAL MICROVASCULAR ISCHEMIA IDENTIFIED BY NEUROIMAGING 39 If we exclude the two patients with pupil involving third nerve palsies as they are much more apt to meet the threshold for imaging and work-up in expert hands, (although pupil involvement is increasingly recognized in diabetic third nerve palsies) we still found seven patients or 11% to have important diagnoses. These included meningiomas, brainstem infarcts, posterior communicating artery aneurysm, demyelinating disease and pituitary apoplexy. This hit rate of 11% was compelling especially for patients with third and sixth nerve palsies. This rate of positive findings compares favorably to other large series of patients that neuroophthalmologists encounter. For instance, this rate is much higher than other common indications for neuroimaging in neuroophthalmic practice including eye pain or face pain, (<2% Harooni et al), non-localizing headache with a normal neurologic exam, 75 and isolated optic atrophy (although one study found a 20% rate of lesion identification, certain clinical predictors were present that made the yield much higher in several patients including bilaterality, progressive vision loss and hemianopic defects), 76 or unexplained vision loss without a localizing visual field defect. In addition, in our nine patients reported, the acute finding modified the patient s initial management including the initiation of high dose steroids for possible Addisonian crisis, work-up with MR angiography because of abnormal vascular studies, echocardiography and antiplatelet therapy or anticoagulation in patients with brainstem infarcts and finally, the initiation of immunomodulatory therapy because of an isolated demyelinating event with positive brain MRI. It is now well recognized that patients with brainstem strokes represent a heterogeneous group of patients, not only with small vessel ischemic disease but potential cardiac and large vessel thromboembolic sources. 77,78 Simply stated, these were high stakes diagnoses that would have been missed or delayed without work up. The results of this study suggest that initial evaluation of even older adults with vasculopathic risk factors who present with cranial nerve palsies has a high enough yield to make this indicated, certainly in third and sixth nerve palsies and perhaps as well in fourth nerve palsies. These patients can not be distinguished by the temporal aspects of their presentation. This significant yield is the result of the quality and detail images that are now available on modern MRI studies. THE DEBATE The debate over whether imaging should be obtained acutely in isolate cranial mononeuropathies thus becomes much more interesting over the last fifteen years when we as a group of experts recognized and reported several of the above referenced, interesting and important etiologies for isolated cranial mononeuropathies in patients that might have otherwise been thought to have a vasculopathic palsy. This has been facilitated by high quality neuro imaging studies. In the 70 s and 80 s when all we had was CT Scan, the small ischemic and inflammatory intraaxial lesions and space occupying lesions that could now be demonstrated on MRI scan were rarely found. The neuroophthalmologist who assumed the position that the vasculopathic patient with isolated cranial nerve palsy required no testing, was secure in his or her position because there was no study capable of identifying potentially important findings. Now in the era of modern magnetic resonance imaging, the expert who chooses not to image these patients has three arguments to rely on; socioeconomic, intellectual and the risks benefits ratio. Socioeconomic: The first argument not to image, is that ordering these relatively low yield tests unnecessarily uses resources, which is certainly important in the climate of escalating health care costs and in locations where diagnostic tests (MRI) are not readily available. Each physician must consider the above argument in the context of all studies ordered during neuro-ophthalmic practice were it to get to a point where these studies were not easily obtained. We recently looked at a consecutive series of all MRIs ordered and identified a yield of relevant findings in 28% of 190 ordered MRIs (147 patients). The highest yield was for demyelinating lesions in setting of optic neuritis although 5 patients with cranial nerve palsies had positive findings including two with strokes, one with Tolosa Hunt, one with sarcoidosis and one with a metastatic lesion. 79 Secondarily, the argument can certainly be employed that work-up can be delayed to the point at which patients don t recover and then (with a much higher yield) anything discovered at that point, probably would have not mattered had it been discovered two or three months earlier. Intellectual: The argument that we know better is a faulty one if we acknowledge that there will indeed be circumstances under which our modern imaging studies will disclose important causes of cranial nerve palsies and the rate at which such findings are identified may be higher than expected since so many patients until now have not been imaged and the quality of our studies continues to improve. 102 North American Neuro-Ophthalmology Society

5 Risks/benefits: MRI scanning is often not an option because of metallic foreign bodies (pacemakers) in this elderly cohort and that some risk to renal function has been recognized from gadolinium injection. There is as well a productivity risk to a physician s staff given the significant resources that are extended to set up and pre certify these tests. ADDITIONAL CONSIDERATIONS In addition to the prospective data, there are three other reasons to consider using neuroimaging at the initial evaluation. The first, and perhaps most important to the rest of the non-expert world, is the message we send if we teach that these can be always safely be followed. In order to successfully follow patients without imaging studies, it requires a level of expertise and a sufficient amount of experience to know when atypical features are present to avoid missing potentially life-threatening or catastrophic diagnoses. At the very least it is probably prudent to consider the non-neuroophthalmologist, neurologist or ophthalmologist as one less able to recognize the nuisances and our message should be either consult with neuroophthalmologist or obtain imaging studies. Second, as imaging studies evolve, including the types of imaging studies. as well as the detail that becomes available on these studies, it is very likely, that one of us in this society will make an important observations about the pathogenesis of this condition as it relates to other ischemic processes. Asbury et al, 2 stated, in 1970, the factors responsible for precipitating the mononeuropathy at a particular time and the factors that allow for remyelination and recovery remain obscure. This is still true 38 years later. Even for the presumed vasculopathic palsies, we may very well be able to begin to identify ischemic changes within the nerve and/or demyelinating changes that will help us to understand the pathogenesis of this and other ischemic conditions, particularly as imaging studies evolve to include higher resolution and metabolic markers. Lastly, of course, and most difficult to argue, but ever present would be the medical legal implications of either missing or delaying the diagnosis. Certainly a delayed diagnosis of a brain stem stroke or pituitary apoplexy that then leads to a more serious event or complication, would potentially put the neuroophthalmologist in an at risk situation. While this is never an appealing argument in terms of the intellectual and evidence based aspects of our practice, it is a very real part of decision making, as are the cost effectiveness and availability of tests as we consider ordering them. SUMMARY In the end each physician makes an individual decision based on the patient, the information presented to them and their own personal experiences and preferences. There is obviously no simple answer to this question but it is important to appreciate that there are a significant minority of patients in the vasculopathic age group that have important, diagnosable conditions, seen on modern neuroimaging studies with therapeutic implications. The likelihood is that the study ordered in this setting will be normal and not contribute to the patient s management. In a previous era when MRI imaging was not available, then the chance to save a patient a risky and invasive procedure was certainly an important role for the neuroophthalmologist who knew better. On the other hand, that argument does not play in the setting in which MRI scan is readily available and providing us with increasingly detailed information about our patients, their diseases and our opportunities to treat them. In addition to the intellectual argument other arguments against imaging these patients include the cost, the burden that ordering these tests places on an already taxed system, the increasing inconvenience factors that exist with setting up MRI scans including hurdles such as precertification from insurance companies and the now acknowledged small risk to renal function of gadolinium injections. The following cases will be presented for audience participation through the audience response system. 1. What tests would you order in a 55-year-old diabetic with partial pupil sparing third nerve palsy with mild headache and no other symptoms? 2. What tests would you order in a 64 year old, trial attorney, with a 10 year history of diabetes and hypertension presenting with a mild forehead ache and isolated sixth nerve palsy? 3. What tests would you order in an 80-year-old diabetic with a complete pupil sparing third nerve palsy? 4. What tests would you order in a 46-year-old insulin dependent diabetic (for the past 20 years) with painless isolated sixth nerve palsy? 5. What tests would you order for an 80 year old man with no significant past medical history who presents with an isolated fourth nerve palsy with poor fusional amplitudes and no inferior oblique overaction? 6. What tests would you order for a 50 year old diabetic with history of uveitis in the left eye presenting with a painless complete left third nerve palsy but miotic pupils with posterior synechiae prevents adequate pupillary evaluation? 7. What tests would you order for a 57 year old man with a history of hyperlipidemia presents with mild discomfort around the right eye with right sixth nerve palsy? 2009 Annual Meeting Syllabus 103

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