Misdiagnosis of Third Nerve Palsy

Background: This study identifies the diagnostic errors leading to misdiagnosis of 3rd nerve palsy and to aid clinicians in making this diagnosis. The objective of this article is to determine the incidence of misdiagnosis of 3rd cranial nerve palsy (3rd nerve palsy) among providers referring to a tertiary care neuro-ophthalmology clinic and to characterize diagnostic errors that led to an incorrect diagnosis. Methods: This was a retrospective clinic-based multicenter cross-sectional study of office encounters at 2 institutions from January 1, 2014, to January 1, 2017. All encounters with scheduling comments containing variations of '3rd nerve palsy' were reviewed. Patients with a documented referral diagnosis of new 3rd nerve palsy were included in the study. Examination findings, including extraocular movement examination, external lid examination, and pupil examination, were collected. The final diagnosis was determined by a neuro-ophthalmologist. The Diagnosis Error Evaluation and Research (DEER) taxonomy tool was used to categorize the causes of misdiagnosis. Seventy-eight patients referred were for a new diagnosis of 3rd nerve palsy. The main outcome measure was the type of diagnostic error that led to incorrect diagnoses using the DEER criteria as determined by 2 independent reviewers. Secondary outcomes were rates of misdiagnosis, misdiagnosis rate by referring specialty, and examination findings associated with incorrect diagnoses. Results: Of 78 patients referred with a suspected diagnosis of 3rd nerve palsy, 21.8% were determined to have an alternate diagnosis. The most common error in misdiagnosed cases was failure to correctly interpret the physical examination. Ophthalmologists were the most common referring provider for 3rd nerve palsy, and optometrists had the highest overdiagnosis rate of 3rd nerve palsy. Conclusions: Misdiagnosis of 3rd nerve palsy was common. Performance and interpretation of the physical examination were the most common factors leading to misdiagnosis of 3rd nerve palsy.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Misdiagnosis of Third Nerve Palsy Richard M. Schroeder, MD, Leanne Stunkel, MD, Mangayarkarasi Thandampallayam Ajjeya Gowder, MD, Emerson Kendall, DO, Bradley Wilson, Lina Nagia, DO, Eric R. Eggenberger, DO, Gregory P. Van Stavern, MD Background: This study identifies the diagnostic errors leading to misdiagnosis of 3rd nerve palsy and to aid clinicians in making this diagnosis. The objective of this article is to determine the incidence of misdiagnosis of 3rd cranial nerve palsy (3rd nerve palsy) among providers referring to a tertiary care neuro-ophthalmology clinic and to characterize diagnostic errors that led to an incorrect diagnosis. Methods: This was a retrospective clinic-based multicenter cross-sectional study of office encounters at 2 institutions from January 1, 2014, to January 1, 2017. All encounters with scheduling comments containing variations of “3rd nerve palsy” were reviewed. Patients with a documented referral diagnosis of new 3rd nerve palsy were included in the study. Examination findings, including extraocular movement examination, external lid examination, and pupil examination, were collected. The final diagnosis was determined by a neuro-ophthalmologist. The Diagnosis Error Evaluation and Research (DEER) taxonomy tool was used to categorize the causes of misdiagnosis. Seventy-eight patients referred were for a new diagnosis of 3rd nerve palsy. The main outcome measure was the type of diagnostic error that led to incorrect diagnoses using the DEER criteria as determined by 2 independent reviewers. Secondary outcomes were rates of misdiagnosis, misdiagnosis rate by referring specialty, and examination findings associated with incorrect diagnoses. Departments of Ophthalmology and Visual Sciences (RMS, LS, BW, GPVS) and Neurology (LS, GPVS), Washington University School of Medicine, St. Louis, Missouri; Department of Neurology and Ophthalmology (MTAG, EK, LN), Michigan State University, East Lansing, Michigan; and Department of Neurology and Ophthalmology (ERE), Mayo Clinic, Jacksonville, Florida. Supported in part by an unrestricted grant from the Research to Prevent Blindness organization to the Washington University in St. Louis Department of Ophthalmology and Visual Sciences. This work was also supported by the National Eye Institute of the National Institutes of Health under award number P30EY002687. This work was presented at the North American NeuroOphthalmology Society 44th and 45th annual meetings, March 6 2018, Waikoloa Village, HI; and March 19 2019, Las Vegas, NV. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8096, St. Louis, MO 63110; E-mail: [e-mail] Schroeder et al: J Neuro-Ophthalmol 2022; 42: 121-125 Results: Of 78 patients referred with a suspected diagnosis of 3rd nerve palsy, 21.8% were determined to have an alternate diagnosis. The most common error in misdiagnosed cases was failure to correctly interpret the physical examination. Ophthalmologists were the most common referring provider for 3rd nerve palsy, and optometrists had the highest overdiagnosis rate of 3rd nerve palsy. Conclusions: Misdiagnosis of 3rd nerve palsy was common. Performance and interpretation of the physical examination were the most common factors leading to misdiagnosis of 3rd nerve palsy. Journal of Neuro-Ophthalmology 2022;42:121–125 doi: 10.1097/WNO.0000000000001010 © 2020 by North American Neuro-Ophthalmology Society O culomotor nerve palsy (3rd nerve palsy) is a neuroophthalmic condition characterized by damage to the main ocular motor nerve, which innervates eyelid elevation, eye movements, and pupillary function. The incidence of 3rd nerve palsy has been estimated in one study to be 4 in 100,000 (1). Although most 3rd nerve palsies are caused by microvascular disease (1), this condition can have more urgent etiologies, including giant cell arteritis, aneurysmal compression, stroke, neoplasm, or Tolosa–Hunt syndrome. Accurate diagnosis through clinical history, pupillary examination, and extraocular movements is essential, both to avoid life threatening consequences to the patient and to avoid unnecessary testing, which can be costly and invasive. Neuroimaging is frequently a component of the workup once 3rd nerve palsy is suspected, to rule out compressive lesions. Characteristic symptoms of diplopia, ptosis, and pupil involvement are correctly emphasized in medical training. Despite this, the authors’ experience suggests that 3rd nerve palsy is frequently misdiagnosed. A diagnostic error is an increasingly recognized problem in medicine, some of which leads to patient harm (2). In one study, not only did 42% of surveyed members of the public report errors in their own or a family members’ care 121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution but also 35% of physicians themselves had experienced diagnostic errors in their own family’s health care (3). A number of studies have addressed diagnostic errors in neuro-ophthalmology, specifically diagnostic errors in idiopathic intracranial hypertension, optic neuritis, and optic nerve meningioma (4–6). A multitude of factors have been proposed in these and similar studies in other specialties as follows: overconfidence, diagnostic heuristics, incomplete examination, premature closure of the case, and failure to synthesize available information (4,6,7). For the purposes of this article, “misdiagnosis” is assigned to patients who were initially diagnosed with 3rd nerve palsy but ended with a different diagnosis. The Diagnosis Error Evaluation and Research (DEER) classification system is a tool to categorize types of diagnostic errors by the location in the diagnostic process where a problem occurred (4,5). The major categories of errors in this system are access to care, history, physical examination, testing, assessment, and consultation. This taxonomy system has been used in recent studies in misdiagnosis of neuro-ophthalmic disorders (4,5) For example, a study of the misdiagnosis of optic neuritis showed that 60% of patients sent to neuro-ophthalmology for a presumed diagnosis of optic neuritis were found to have alternative diagnoses, and the most common error leading to misdiagnosis was in eliciting or interpreting critical elements of history (6). The objective of this study is to use the DEER criteria to identify diagnostic errors that contribute to a misdiagnosis of 3rd nerve palsy and to characterize factors contributing to these errors. Our suspicion has been that a diagnosis of 3rd nerve palsy is made too quickly when a patient presents with new manifest strabismus without considering a broader differential diagnosis. By analyzing the causes of diagnostic errors, we hope to identify avenues to reduce medical errors in the future and to prevent unnecessary harm to patients in the form of unnecessary testing and psychological distress. METHODS Institutional Review Board approval was obtained at the Washington University in St. Louis’s Human Research Protection Office and at the Michigan State University Human Research Protection Program. The research adhered to the tenets of the Declaration of Helsinki. New patient encounters occurring at neuroophthalmology clinics at 2 academic institutions between January 1, 2014 and January 1, 2017 were retrospectively reviewed (Table 1). All new patient visits have scheduling comments in the electronic medical records system with the reason for referral. These comments were searched for variations of “3rd nerve palsy,” for example, “oculomotor nerve palsy,” “CN3 palsy,” “CNIII palsy,” etc. In all cases, referral notes from the physician or optometrist who sent the patient for consultation were available for review. If the referral notes confirmed that the referring provider had 122 made a diagnosis of 3rd nerve palsy, they were included in the study. Patients with inadequate referral documentation (did not clearly state the diagnosis) or who were referred for management of long-standing and well-known 3rd nerve palsy were excluded. All patients received a thorough history and full neuroophthalmic examination as part of the standard of care at the tertiary referral centers. Demographic data, including age, gender, specialty of referring provider, and previous diagnostic studies were recorded. Data collected from the neuro-ophthalmology visits also included pertinent history, physical examination findings, and final diagnosis (Table 2). Final diagnosis by a fellowship-trained neuroophthalmologist was defined as the “correct” diagnosis. In most cases, a clinical examination with emphasis on extraocular movements, alternate cover test, and pupil examination was sufficient for the diagnosis. In some cases, additional laboratory or imaging testing was ordered to evaluate for other etiologies (thyroid panel, myasthenia antibodies, etc.). If additional testing was ordered on the initial neuro-ophthalmology visit, the final diagnosis was recorded after that workup was completed. For patients who were found to have any alternate diagnosis (a final diagnosis that was not 3rd nerve palsy), the DEER criteria was applied to categorize the diagnostic error based on the referral documentation. Each case was reviewed by 2 separate graders working independently (R.S., L.S. and E.K., M.G.). Every effort was made to identify the root cause for misdiagnosis, when multiple categories of error could be identified. When the 2 evaluators did not agree, the case was further reviewed by G. P. Van Stavern or L. Nagia to make a final categorization. The mean SD and range are reported for continuous measures. Comparisons between the groups diagnosed with 3rd nerve palsy and the group not diagnosed with 3rd nerve palsy were conducted using 2-group t tests. For categorical measures, percentages are reported and the comparisons are conducted using the Fisher exact test. Statistical analyses were performed using Microsoft Excel (Seattle, WA) and SAS version 9.4; SAS Inc, (Cary, NC). RESULTS Of the 78 patients included in the study, 61 patients (78.2%) were diagnosed with 3rd nerve palsy. The remaining 17 patients (21.8%) were originally diagnosed by the referral provider with partial 3rd nerve palsy or did not specify complete vs partial palsy but were found to have alternate etiologies of their symptoms. These diagnoses were decompensated strabismus, myasthenia gravis, fourth nerve palsy, sixth nerve palsy, internuclear ophthalmoplegia, monocular diplopia, thyroid eye disease, and foveal drag syndrome. There were no significant differences in the demographics of these 2 groups (Table 1) besides a higher Schroeder et al: J Neuro-Ophthalmol 2022; 42: 121-125 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics 3rd Nerve Palsy Diagnosis Confirmed, N = 61 Found to Have Alternate Diagnosis, N = 17 Mean: 63.0 SD = 15.2 Median: 66 Range: 17–85 23 (38%) 38 (62%) 24 (39%) 28 (46%) 32 (52%) 49 (80%) 39 (64%) Mean: 61.4 SD = 16.2 Median: 67 Range: 22–81 10 (59%) 10 (59%) 0 (0%) 5 (29%) 9 (53%) 14 (82%) 9 (53%) Age Gender (female) History of hypertension History of smoking History of diabetes History of hyperlipidemia Race (Caucasian) MRI before consult P value* 0.705 0.166 0.786 0.0009 0.275 1 1 0.416 The Fisher exact test for categorical variables. *T test for continuous variables. incidence of tobacco users in the group that was diagnosed with 3rd nerve palsy (P = 0.0009). Multiple medical specialties referred patients with suspected 3rd nerve palsies to the neuro-ophthalmology clinic, including ophthalmology, neurology, internal medicine, neurosurgery, and rehabilitation medicine (Table 2). Patients were most often referred by other ophthalmologists. Among providers, optometrists were most likely to refer a patient for 3rd nerve palsy evaluation who ultimately received an alternate diagnosis. Physical examination findings were recorded from the neuro-ophthalmology visit (Table 3). There were significant differences in the extraocular movements of patients who were ultimately diagnosed with 3rd nerve palsy and those who were not. Patient’s with physical examination findings of an elevation deficit (P = 0.0079), depression deficit (P = 0.0017), or exotropia (P = 0.00018) were more likely to have a confirmatory diagnosis of 3rd nerve palsy. Examination findings that were not significantly different after adjustment for multiple comparison between the 2 groups were diplopia (P = 1), ptosis (P = 0.441), pupil involvement (P = 0.144), and adduction deficit (P = 0.207). Patients ultimately diagnosed with 3rd nerve palsy were usually those who presented with a “classic” combination of adduction, elevation, and depression deficits (P = 0.00045). The type of diagnostic errors was categorized using the DEER criteria (Table 4). Most of the diagnostic error in this study related to the interpretation of physical examination findings (71%). In 5 patients, the referring provider did not elicit a critical examination finding. Most of these errors (3 of 5) occurred in patients who did not receive a full extraocular muscle examination with an alternate cover test. Frequently, an adduction deficit was noted without any comment on vertical eye movements. In 6 patients the critical examination finding was elicited but was interpreted incorrectly resulting in a misdiagnosis. For example, in one patient’s referral documentation, a fully comitant pattern of exotropia was documented but was diagnosed with 3rd nerve palsy. Schroeder et al: J Neuro-Ophthalmol 2022; 42: 121-125 In 3 patients there was a failure in eliciting, interpreting, or weighing the patient history. In 2 cases there was an error in the formulation and weighing of a differential diagnosis leading to an inappropriate diagnosis of 3rd nerve palsy. For example, ocular myasthenia was missed as a diagnosis. The intermittent nature of extraocular motions was not prioritized, and ocular myasthenia was not considered. DISCUSSION Of the 78 patients included in this study, 21.8% had been misdiagnosed with 3rd nerve palsy by their referring provider. There were significant differences in the examination findings between the 2 groups, and failure to elicit or interpret a proper examination was the most common DEER criteria identified in misdiagnosis. Thus, the technique of performing and interpreting of the physical examination seems to be a major determining factor for patients to be diagnosed correctly. The classic findings of 3rd nerve palsy are ptosis, pupil involvement, and motility deficits. Specifically, the oculomotor nerve is responsible for elevation, depression, and adduction of the globe. Those correctly diagnosed with 3rd nerve palsy were more likely to have ptosis and pupillary TABLE 2. Overdiagnosis rates by specialty of referral source Specialty Ophthalmology Optometry Neurology Internal medicine Family medicine Neurosurgery Rehabilitation medicine 39 10 17 6 3 1 1 No. of Referrals Overdiagnosis Rate of of of of of of of 7 of 39 (18%) 7 of 10 (70%) 2 of 17 (12%) 1 of 6 (17%) 0 of 3 (0%) 0 of 1 (0%) 0 of 1 (0%) 78 78 78 78 78 78 78 (50%) (13%) (22%) (8%) (4%) (1%) (1%) 123 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Examination findings 3rd Nerve Palsy Diagnosis Confirmed, N = 61 Diplopia Ptosis Pupil involvement Adduction deficit Elevation deficit Depression deficit Exotropia Hypertropia Adduction, elevation, and depression deficit 58 42 22 44 39 39 52 32 37 (95%) (69%) (36%) (72%) (64%) (64%) (85%) (52%) (61%) Found to Have Alternate Diagnosis, N = 17 16 7 1 7 3 2 5 11 1 (94%) (41%) (6%) (41%) (18%) (12%) (29%) (65%) (6%) P value (Fisher Exact Test) P value* 1 0.049 0.016 0.023 0.0009 0.0002 ,0.0001 0.42 ,0.0001 1 0.441 0.144 0.207 0.0079 0.0017 0.00018 1 0.00045 *Adjusted for multiple comparisons with Bonferroni correction. involvement; however, when adjusted for multiple comparisons, both of these differences lost statistical significance. A presenting symptom of diplopia did not reach statistical significance in predicting a final diagnosis of 3rd nerve palsy. The lack of significance of these particular findings emphasizes that referring providers should not make a diagnosis based on the presence of ptosis and diplopia alone but should also include a thorough motility examination. Performing and interpreting the physical examination was a common source of error. Frequently, a diagnosis of 3rd nerve palsy was made in a patient that did not have a consistent pattern of disease, such as a comitant motility deficit. Some patients referred for 3rd nerve palsy even had a normal motility examination. Patients in this study who had all 3 classic motility elements of 3rd nerve palsy—elevation deficits, depression deficits, and exotropia—were much more likely to have a final diagnosis of 3rd nerve palsy than patients who did not have all 3. An adduction deficit was equally present in both groups that may be explained by the presence of adduction deficits in alternate diagnoses, such as myasthenia, internuclear ophthalmoplegia, and thyroid eye disease. These findings emphasize that a diagnosis of 3rd nerve palsy should be questioned if the patient does not demonstrate a combination of expected deficits in elevation, depression, and adduction. It is worth noting that an incorrect diagnosis can lead to patient inconvenience or even harm. In this study, 53% of patients who were found to have an alternative diagnosis from 3rd nerve palsy had been imaged with an MRI before consultation. Although in some cases this may have been warranted, MRI testing can be costly to patients and lead to false positives. Although difficult to quantify, the psychological component of a diagnosis with 3rd nerve palsy is significant and can lead to patient distress unnecessarily. There are several limitations to this study. As our population was limited to patients referred to tertiary care neuro-ophthalmology clinics, these may represent more complex cases with more diagnostic challenge. This study does not capture the entire population of patients with 3rd nerve palsy—patients who were diagnosed and managed without referral to neuro-ophthalmology were not captured. Next, DEER criteria assignment is inherently subjective. At times, a misdiagnosis could very reasonably be attributed to multiple portions of the history, examination, and assessment. In each case the graders tried to identify the most prominent reason that the wrong diagnostic path was taken. There is room for improvement in the diagnostic process for 3rd nerve palsy. Careful attention to the performance and interpretation of a detailed motility examination is the highest TABLE 4. Categorization of types of diagnostic errors in patients with final diagnoses other than 3rd nerve palsy Type of Diagnostic Errors Error in eliciting or interpreting critical elements of history Failure/delay in eliciting history Inaccurate/misinterpreted history Failure in weighing the history Error weighing or interpreting physical examination findings Failure to elicit critical examination finding. Inaccurate/misinterpreted examination. Failure in weighing examination Failure in considering other diagnoses. Failure to consider diagnosis. Too little weight on competing diagnosis Total 124 Absolute Count 3 1 1 1 12 5 6 1 2 1 1 17 Percentage 18 71 12 100 Schroeder et al: J Neuro-Ophthalmol 2022; 42: 121-125 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution yield area for improvement, particularly regarding the alternate cover test and vertical deficits. A normal or at least comitant motility examination is a reassuring finding when evaluating for 3rd nerve palsy. Attention to these areas can better aid clinicians in triaging and treating patients with this concerning disease process and help prevent unnecessary, costly, and invasive diagnostic testing. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: L. Nagia, E. R. Eggenberger, and G. P. Van Stavern; b. Acquisition of data: R. M. Schroeder, L. Stunkel, M. T. A. Gowder, and E. Kendall; c. Analysis and interpretation of data: R. M. Schroeder, L. Stunkel, M. T. A. Gowder, E. Kendall, B. Wilson, L. Nagia, E. R. Eggenberger, and G. P. Van Stavern. Category 2: a. Drafting the manuscript: R. M. Schroeder; b. Revising it for intellectual content: R. M. Schroeder, L. Stunkel, M. T. A. Gowder, E. Kendall, B. Wilson, L. Nagia, E. R. Eggenberger, and G. P. Van Stavern. Category 3: a. Final approval of the completed manuscript: R. M. Schroeder, L. Stunkel, M. T. A. Gowder, E. 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