Case
A 65 year old white male with hypertension, diabetes, and hyperlipidemia presents with acute, painless, binocular horizontal diplopia. The visual acuity is 20/20 (6/6) OU and the pupil examination is normal. On motility examination there is an abduction deficit in the right eye (OD) with an incomitant esotropia (ET) of 40 prism diopters worse in right gaze (60 ET). The left eye moved normally. The fundus exam was normal OU. The remainder of the neurologic and ophthalmologic examinations were normal.
Introduction
The decision to obtain early neuroimaging for patients with acquired neurologically isolated sixth nerve palsy has been a topic of debate in past years. In patients over age 50, the most common cause of a neurologically isolated sixth nerve palsy is presumed microvascular ischemia and is associated with vascular risk factors including hypertension, hyperlipidemia and diabetes [1]. In the majority of these patients, neuroimaging is unrevealing, and the ocular motor palsy usually resolves within 3–6 months without intervention or any adverse outcomes. Traditional teaching has been to defer immediate neuroimaging and observe for spontaneous resolution of a neurologically isolated, presumed vasculopathic, ocular motor palsy over several months. Resolution is generally accepted as clinically diagnostic of a vasculopathic origin. In contrast, among patients younger than age 50 years (an arbitrary threshold), other more serious causes of sixth nerve palsy, including intracranial neoplasms, brainstem infarction, infection and demyelinating disease are more common, and there is generally uniform consensus that immediate neuroimaging is warranted.
Proponents of deferring immediate neuroimaging in older adults with vasculopathic risk factors argue that ordering MRI scans in this cohort of patients is low yield, expensive, and contributes to the wasteful overutilization of unnecessary tests. Obtaining MRI scans on all patients may also increase the likelihood of discovering incidental but otherwise benign findings that could lead to further imaging and more invasive testing. This teaching, however, is based in an era of neuroimaging before the development of MRI, in which imaging modalities such as CT scans, pneumoencephalograms and catheter arteriograms were more invasive and carried greater risks and in which a careful clinical exam could spare the patient from undergoing painful, low-yield procedures.
With the development of MRI, a number of non-ischemic etiologies, including potentially life threatening, treatable or clinically relevant pathologies have been identified on neuroimaging of patients over age 50 with isolated sixth nerve palsies that may have otherwise been missed or attributed incorrectly to microvascular ischemia. In most situations the presentation of these patients is clinically indistinct from simple vasculopathic palsies. Recognizing that there is a small but significant possibility of an alternative cause for isolated sixth nerve palsies in this age group and the medical and legal implications of a missed or delayed diagnosis should prompt a reexamination of traditional clinical dogma and reconsideration of whether early neuroimaging for older patients, even in the presence of vasculopathic risk factors, may be favored.
The objective of this chapter is to review the clinical features and causes of sixth nerve palsies and to examine the role of neuroimaging in the diagnosis and management of these patients.
Clinical Features and Causes
Sixth nerve palsy is the most common ocular motor nerve palsy, with an incidence of about 11.3/100,000 per year [2, 3]. Patients with unilateral isolated sixth nerve palsy present with binocular horizontal diplopia and an abduction deficit of the ipsilateral eye. Causes of sixth nerve palsy range from benign, such as microvascular ischemia, to more serious pathologies, such as neoplasm, pituitary apoplexy, brainstem strokes, trauma, infection, demyelinating disease, aneurysms, giant cell arteritis and intracranial hypertension. The most common causes for acquired neurologically isolated sixth nerve palsy vary depending on the age of the patient. In adults over age 50, most cases of isolated sixth nerve palsy are due to presumed microvascular ischemic demyelination, and these patients should be questioned about a history of vasculopathic risk factors, including diabetes mellitus, hypertension, hyperlipidemia and smoking. Patients with a microvascular ischemic ocular motor nerve palsy typically experience significant pain around the eye. Spontaneous recovery of the nerve palsy within several months of onset and without the development of any new neurologic signs during the follow-up period is considered evidence of a vasculopathic etiology. In one study, 87% of patients with acquired isolated sixth nerve palsy due to any cause had partial recovery of motor function at 6 months after initial onset and 73% had complete recovery at 6 months [2].
However, spontaneous resolution of the ocular motor palsy does not necessarily exclude alternative etiologies. Other well-established causes of sixth nerve palsy in adults over age 50 include pontine infarctions and hemorrhages [4–6], which may be expected to self-resolve with time, as well as skull base tumors, such as meningiomas [7, 8], chordomas [9], nasopharyngeal carcinomas [10] and others [11, 12]. Skull base tumors have been observed to present as a spontaneously recovering abduction deficit [13]. Autoimmune inflammatory disorders such as chronic inflammatory demyelinating polyneuropathy have also been reported to present as a remitting-relapsing abducens nerve palsy [14].
While pain is a common feature of microvascular ischemia, it is not specific to any particular etiology and may suggest ischemic or inflammatory causes, infection, intracranial hypertension, or an orbital lesion. Older patients should be questioned about symptoms of giant cell arteritis, including temporal headache, jaw claudication, weight loss, fatigue, fever and vision loss, and laboratory work including C-reactive protein and erythrocyte sedimentation rate should be ordered if there is clinical suspicion. Other “red flags” such as a history of cancer, autoimmune disease, immunosuppression, fluctuating or progressive diplopia, or the presence of other neurologic signs or symptoms, should raise suspicion for etiologies other than microvascular ischemia.
In patients under age 50 with isolated sixth nerve palsies, non-microvascular ischemic causes occur with greater frequency. In one study, central nervous system space-occupying lesions and multiple sclerosis accounted for a majority of causes of sixth nerve palsies in patients 20–50 years old [15]. Other etiologies include viral infection, meningitis, idiopathic intracranial hypertension, trauma, cavernous sinus fistulas and intracavernous aneurysms [16–19], metastases [20], and pituitary apoplexy [21], with more unusual reported associations including central pontine myelinolysis [22], varicella [23], and dengue fever [24]. Given the higher likelihood of more serious pathologies, the acute onset of isolated sixth nerve palsy in younger patients should not be readily attributed to presumed microvascular disease.
Utility of Neuroimaging
Summary of studies examining yield of MRI scans in isolated ocular motor palsies
Study | Age, years | Total patients | No. of pts. with isolated VI nerve palsy | Positive scan results | Negative scan results | Reported causes |
|---|---|---|---|---|---|---|
Bendszus et al. (2001) [28] | Any age; mean 48; range 2–82 | 43 | 43 | 27 (63%) | 16 (37.2%) | Tumors (metastasis, meningioma, glioma, chordoma), sarcoidosis, aneurysm |
Chou et al. (2004) [26] | ≥50; median 67; range 50–85 | 66 | 23 | 4 (17.3%) | 19 (82.6%) | Meningioma, brainstem infarct, multiple sclerosis, pituitary apoplexy |
Murchison et al. (2011) [27] | ≥50 (median and range not specified) | 93 | 52 | 4 (8.3%); only 1 (2.1%) with lesion consistent with CN VI | 48 (92.3%) | Pontine hemorrhage |
Tamhankar et al. (2013) [25] | ≥50; median 64; range 50–90 | 109 | 62 | 12 (19.4%) | 50 (80.6%) | GCA, cavernous sinus B-cell lymphoma, petroclival meningioma |
Similar “yields” on neuroimaging were found in a 2004 study, in which 9 of 66 patients (14%) over age 50 with acute isolated ocular motor palsy were found to have a causative lesion on MRI [26]. Of 23 patients specifically with isolated sixth nerve palsies, 4 (17.4%) were diagnosed with a non-microvascular ischemic etiology following imaging [26]. These causes were neoplasm, brainstem infarct, multiple sclerosis and pituitary apoplexy. While the presence of at least one vasculopathic risk factor (e.g., diabetes, hypertension, hyperlipidemia and coronary artery disease) was significantly associated with a microvascular etiology, vasculopathic risk factors were still present in 56% of patients with etiologies other than peripheral microvascular ischemia.
The likelihood of identifying a non-microvascular ischemic cause of isolated ocular motor palsy on MRI was much lower in a 2011 study by Murchison et al. [27]. Among 93 patients over age 50, only 1 (1.1%) was found to have a lesion (a pontine hemorrhage) on neuroimaging that could explain a sixth nerve palsy.
In contrast, in a 2001 study of patients of any age presenting with isolated unilateral sixth nerve palsy, 63% were found to have a cause other than presumed microvascular ischemia, including tumors (e.g., meningioma, pontine glioma, chordoma, chondrosarcoma, schwannoma, craniopharyngioma, and pituitary adenoma), sarcoidosis, and cavernous sinus aneurysm [28]. Ages of subjects included in this study ranged from 2 to 82 years, with a median age of 43 years. As expected, the younger cohort of patients in this study significantly increased the chances of identifying a causative lesion on MRI. If considering only patients with a history of vasculopathic risk factors, the yield of MRI in identifying other non-microvascular ischemic causes was 15%; the median age of this cohort was 48 years.
These studies shed light on the frequency of non-microvascular ischemic etiologies for isolated ocular motor nerve palsies and the likelihood that vasculopathic patients with neurologically isolated sixth nerve palsy may harbor an identifiable lesion on neuroimaging to explain their cranial neuropathy. However, they also highlight difficulties in drawing conclusions from such studies and applying these findings to clinical practice, given the variability of patient acuity and study centers (e.g. primary vs. tertiary referral centers) across studies. Collectively, the studies suggest there is between a 1–15% chance of finding a non-microvascular etiology on neuroimaging in patients with an isolated ocular motor palsy and a history of vasculopathic risk factors. They also underscore the importance of considering age and medical history in the evaluation of the patient as these factors can significantly affect the likelihood of an alternative diagnosis.
Early Neuroimaging for Sixth Nerve Palsy in Older Patients
Formal guidelines for obtaining neuroimaging in the diagnostic evaluation of sixth nerve palsies were published in 1999 [29]. Immediate neuroimaging and further evaluation was recommended for the following classifications of sixth nerve palsies: (1) non-isolated sixth nerve palsy; (2) traumatic sixth nerve palsy (in which there is a clear temporal association between the occurrence of trauma and onset of the sixth nerve palsy); (3) non-vasculopathic sixth nerve palsy; and (4) patients with progressive or non-resolving sixth nerve palsy, or with development of new neurologic signs or symptoms. For patients with vasculopathic risk factors, the recommendation was to defer immediate neuroimaging and observe for improvement within 3 months and to obtain imaging if there was progression or lack of improvement during this time.
The recommendation to defer immediate neuroimaging in the subset of patients above age 50 with isolated sixth nerve palsy and a history of vasculopathic risk factors has remained a point of contention. While most clinicians would agree that neuroimaging should be obtained for patients under age 50 in which there is a greater likelihood of identifying a causative lesion on MRI, in the majority of patients older than age 50 years in which presumed microvascular ischemia is the most common etiology, neuroimaging will be unrevealing. The likelihood of finding an alternate explanation on MRI in this population is about 5%, with exact percentages varying from study to study. Whether the benefits of ordering neuroimaging on all patients in this subset to identify the approximately 5% of individuals with alternative etiologies outweigh its costs is subject to debate.
There is no question that ordering MRIs is expensive. In the 2011 study of 93 patients with isolated ocular motor palsy, Murchison et al. estimated the cost of imaging spent on these patients to be $131,688 [27]. An underlying lesion was found on imaging in only one patient, which did not ultimately change the patient’s management. However, while all clinicians should be cognizant of limiting unnecessary tests and imaging, conservative management must be weighed against what is in the best interests of the patient. Moreover, while the yield of MRI for sixth nerve palsy in vasculopathic patients is low, so is neuroimaging that is routinely ordered for various other neurologic symptoms, such as chronic headaches [30, 31], unexplained eye pain or facial pain [32].
For many of the alternate causes of a sixth nerve palsy, early diagnosis and initiation of therapy is beneficial (antiplatelet or anticoagulation for infarctions; echocardiogram to identify cardiac embolic sources; immunomodulatory therapy for multiple sclerosis). Even in instances where a delay in diagnosis may not necessarily adversely affect the outcome, such as in a slow-growing meningioma, it may affect the patient’s perception of the physician’s clinical judgment.
Lastly, as MRI technology continues to advance, clinicians may be able to more readily identify lesions that were previously below the threshold of detection. Obtaining early neuroimaging for vasculopathic patients may also provide useful information regarding the pathogenesis of microvascular ischemia.
Global Perspective
The causes of acute isolated sixth nerve palsy range from benign and innocent, such as microvascular ischemia, to more serious conditions, such as neoplasms, brainstem infarction, demyelination and infection. Clinicians must weigh a multitude of factors, including the age of the patient, medical history and any subtle signs or nuances on the physical exam, in deciding whether to obtain early neuroimaging. Truly isolated sixth nerve mononeuropathies in patients over age 50 with vasculopathic risk factors are by and large attributable to presumed microvascular ischemia and immediate neuroimaging will generally be unrevealing. While deferring immediate neuroimaging is an acceptable plan of management for this cohort of patients, in about 5% of patients, this will result in a missed or delayed diagnosis. There are many reasons why early neuroimaging for all patients with acute sixth nerve palsy may be advantageous. It is our policy to recommend and offer neuroimaging to all patients after discussing the low but potentially “high stakes” yield of such a study. The decision to defer neuroimaging should be based on an evaluation of the risk factors and pretest likelihood of finding alternate etiologies, careful discussion with the patient about the small (5%) possibility of potentially missed or delayed diagnosis, as well as availability of access to imaging.