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NEURO-OPHTHALMOLOGY: Edited by Dean M. Cestari

Management of acute cranial nerve 3, 4 and 6 palsies

role of neuroimaging

Tamhankar, Madhura A.a; Volpe, Nicholas J.b

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Current Opinion in Ophthalmology: November 2015 - Volume 26 - Issue 6 - p 464-468
doi: 10.1097/ICU.0000000000000200
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The diagnostic evaluation of patients presenting with acute ocular motor cranial mononeuropathies is based on age at presentation, onset and duration of the palsy, associated systemic and neurological symptoms and signs. The traditional teaching in neuroophthalmology has been that older individuals (age>50 years) with acute isolated ocular motor cranial mononeuropathy with microvascular risk factors such as diabetes mellitus, hypertension and hyperlipidemia may be followed without neuroimaging as spontaneous resolution of the palsy is expected in about 8–10 weeks. This teaching originated in the preimaging era when investigative modalities including skull radiographs, polytomography, pneumoencephalography and catheter arteriography were invasive, painful and carried associated risks. Moreover, these techniques were less sensitive in detecting intracranial diseases. Finally, the assumption that the vast majority of these palsies was in fact ischemic mononeuropathies and would simply spontaneously improve is indeed accurate. Prior published studies looking at the natural history of acute-isolated ocular motor cranial mononeuropathies in older adults are based on computed tomography that is less sensitive in identifying intracranial causes for these palsies [1,2][1,2]. Since the development of MRI, less benign and potentially treatable causes for acute ocular motor mononeuropathies have been reported, which include intracranial neoplasm, aneurysms, inflammation, infection and brainstem infarction [3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30]. The prevalence of these findings is different for third, fourth and sixth nerve palsies, and it may ultimately be beneficial to not apply the same recommendations to all patients.

Box 1:
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The patients who present with acute ocular motor mononeuropathies complain primarily of diplopia that may be horizontal, vertical or both. The onset of diplopia may be insidious or acute.

In evaluating such patients who present with diplopia, certain pertinent symptoms and signs should be ascertained in order to arrive at a diagnosis and its localization. Although in many patients, diplopia may be an isolated finding, the examining physician must also determine if there is a history of other neurological signs or symptoms such as headache, dizziness, eye pain, weakness and numbness of face or extremities. A history of vasculopathic risk factors such as diabetes mellitus, hypertension, hyperlipidemia and smoking history should be sought. History of other relevant conditions such as a past history of strabismus, head and/or orbital trauma, prior orbital disease and neurosurgical intervention will offer clues to the cause and should be inquired into.

The diagnosis of third, fourth or sixth cranial nerve palsy can be made on examination of ductions and versions of the eye and an assessment of alignment. Third nerve palsy can be partial or complete and may or may not involve the pupil. Patients present with ptosis and exotropia along with vertical misalignment of the eye. There is variable presence of adduction, elevation and/or depression deficits. The pupil may be involved with the presence of pupil dilatation secondary to disruption of parasympathetic fibers. Pupillary involvement is characterized by a larger pupil (5–7 mm) that is sluggishly reactive on the involved side.

The patients with fourth nerve palsy often present with vertical diplopia characterized by ipsilateral hypertropia that increases in contralateral gaze and ipsilateral head tilt. Ocular ductions often appear full and there may be the presence or absence of inferior oblique overaction on the ipsilateral side of the palsy. Measurement of fusional amplitudes in patients with fourth nerve palsy is important regardless of acute or insidious presentation as large fusional amplitudes suggest a more long-standing misalignment. The presence of excyclotorsion over 5° favors an acute palsy and more than 10–15° (with alternating hypertropia) may indicate bilateral fourth nerve palsy.

Sixth nerve palsy is characterized by the presence of binocular horizontal double vision. Ocular ductions reveal an abduction deficit on the involved side and an incomitant esotropia that increases on attempted abduction to the side of the palsy.

Cause and specific diagnostic considerations

Because of a very high prevalence of structural, infectious and inflammatory causes, the patient's age at presentation is an important consideration in terms of work up for causes. Younger adults (<50) and pediatric patients will need comprehensive evaluation including MRI of the brain and laboratory work up to identify intracranial tumors, infectious or inflammatory causes for the diplopia.

On the other end of the spectrum is the older individual. If there is a suspicion for giant cell arteritis, then information about headaches, jaw claudication, night sweats, weight loss and fever should be sought and further evaluation with laboratory work up including complete blood count, erythrocyte sedimentation rate and C-reactive protein obtained, followed by temporal artery biopsy in suspicious cases [31 ▪▪ ,32][31 ▪▪ ,32].

The presence of eye pain, proptosis or enophthalmos may suggest an orbital cause for the lesion. Ocular myasthenia gravis can mimic a cranial nerve palsy. When there is a variability of presentation, ptosis, bulbar symptoms or proximal muscle weakness, ice test for reversal of ptosis and laboratory testing for acetylcholine receptor antibodies should be obtained.

The causes for acute onset isolated ocular motor cranial neuropathies include presumed microvascular ischemia, compression, inflammation, trauma and neuromuscular junction disorders. However, certain causes are more commonly associated with different ocular motor cranial nerves. For instance, the fourth cranial nerve is commonly involved in closed head injury. The presence of variability of diplopia, large fusional amplitudes, inferior oblique overaction, facial asymmetry and head tilt seen in prior photographs may indicate an acute decompensation of congenital fourth nerve palsy. Some patients may endorse a prior history of episodic diplopia. If such a history is present, then long-standing ocular misalignment should be considered in the differential diagnosis. In pupil involving third nerve palsy, aneurysmal cause is an important consideration and appropriate neuroimaging should be ordered to rule out an intracranial aneurysm. Subtle skull-based lesions can cause relapsing-remitting acute sixth nerve palsies [33 ▪▪ ,34][33 ▪▪ ,34].


The necessary work up and management of acute-isolated ocular motor cranial mononeuropathy in individuals older than 50 years remains somewhat controversial with some advocating for watchful waiting and others recommending immediate neuroimaging.

The frequency of various causes of acute-isolated ocular motor cranial mononeuropathies has been reported in retrospective series in the past [1,35][1,35]. These studies were published before the era of modern neuroimaging; some were hospital-based and suffer from referral bias to tertiary care centers. The prevalence of causes in these older series includes ischemic, aneurysmal, tumor, congenital (for fourth nerve palsies), myasthenia gravis, demyelinating and undetermined cause. Since the advent of MRI, less benign causes potentially requiring treatment have been identified as causes of acute ocular motor mononeuropathies including intracranial neoplasm, aneurysm, inflammation, infection and brain stem infarctions [3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30][3–30]. There remains lack of large-scale prospective population-based age-specific studies to address the diagnostic yield of immediate neuroimaging in the setting of acute-isolated ocular motor mononeuropathies.

Role of neuroimaging

The decision to perform neuroimaging in patients who present acutely with acute ocular motor cranial mononeuropathy is based on age at presentation, which nerve is involved and pertinent past medical history. All patients younger than 50 need evaluation including neuroimaging and laboratory tests to rule out myasthenia gravis. In a recent series looking at causes for sixth cranial nerve palsy in the pediatric population, neoplasm and trauma were the most common causes followed by increased intracranial pressure, inflammation, congenital, dural sinus thrombosis, Guillain–Barré syndrome and demyelination [36]. Prospective studies have shown that in those patients younger than 50 the yield on neuroimaging can be as high as 63% with 27 of 43 patients in one series having significant causative lesions on brain MRI [3].

Incomplete or pupil involving third nerve palsy requires urgent evaluation for the possibility of aneurysm regardless of age. A vascular study such as a computed tomography angiography (CTA), magnetic resonance angiography or digital subtraction angiography should be pursued [37].

With noninvasive neuroimaging such as MRI and CTA now readily available at least in the USA a plethora of case reports that have identified other causes for these palsies and prospective studies identifying a significant prevalence of important and identifiable lesions leads to our recommendation of obtaining MRI on most or all of affected patients [31 ▪▪ ,33 ▪▪ ][31 ▪▪ ,33 ▪▪ ].

Many experts feel that regardless of pupil status and completeness of the palsy, given the exceptions that have been reported, that all patients with third nerve palsy should have MRI and a supplementary study to rule out an aneurysm. For the fourth and sixth nerve palsies, recognizing that the majority of which are due to an ischemic or demyelinating process, most patients have an excellent prognosis for spontaneous recovery over 3 months. The need for immediate neuroimaging is controversial in part because of presumed low yield, to save expense and the belief that delay in neuroimaging does not lead to adverse outcomes [28,38 ▪▪ ,39][28,38 ▪▪ ,39][28,38 ▪▪ ,39].

Four prospective studies have attempted to address the need for early neuroimaging in older adults presenting with isolated acute ocular motor mononeuropathies [3,28,29,31 ▪▪ ][3,28,29,31 ▪▪ ][3,28,29,31 ▪▪ ][3,28,29,31 ▪▪ ]. In one study, the yield of MRI in identifying other causes for sixth cranial nerve palsy was 15% (four patients total; two with metastasis, one with a meningioma and one with aneurysm). The details of past medical history were not provided and the median age of the cohort in this study was 43 years, an age in which there is a higher likelihood of finding a specific cause [3]. A second study of patients over the age 50 by Chou et al.[28] found a 13.6% (nine of 66) incidence of other identifiable causes in patients presenting with acute ocular motor mononeuropathies. Even excluding third cranial nerve palsies from this cohort (as the majority of third cranial nerve palsy patients will undergo neuroimaging regardless of the presence of vasculopathic risk factors), the incidence of other causes for fourth and sixth cranial nerve palsies was 13.5% (five of 37). The causes were neoplasm, brainstem infarction, demyelinating disease and pituitary apoplexy. The patients could not be distinguished by their history or examination, even by experienced neuroophthalmologists. The authors concluded that early neuroimaging should be performed in all patients with an acute ocular motor cranial mononeuropathy. In contrast, a third study by Murchison et al.[29] assessed the yield and cost utility of neuroimaging for acute-isolated ocular motor mononeuropathies in adults over the age of 50 years and found a low prevalence of causative lesions on MRI (1.1%, one of 93 patients). The one patient identified had a sixth cranial nerve palsy from a pontine hemorrhage that did not need intervention. The authors concluded that in older adults with the presence of vasculopathic risk factors, early neuroimaging was not cost-effective. The above two studies were single center studies and excluded all patients with prior history of cancer or neurologic and orbital disease as well as head trauma [28,29][28,29].

A more recent multicenter prospective study assessed the diagnostic yield of neuroimaging in 109 patients presenting with acute third, fourth or sixth nerve palsy and found the overall yield of neuroimaging to be 16.5%, whereas in those patients with fourth and sixth nerve palsy and no significant past medical history, the yield was 4.6% [31▪▪]. The causes included stroke, neoplasm, inflammation and pituitary apoplexy. This study found a one in 20 chances that a patient with vasculopathic risk factors had another cause for the fourth and sixth cranial nerve palsy. Another feature of this study was that the incidence of vasculopathic risk factors between the group that had presumed microvascular ischemia and the group that had other causes was not any significantly different. Therefore, the presence or absence of vasculopathic risk factors cannot help to differentiate those patients who had other causes for their palsy.

The recommendation by the authors was that given the high prevalence of alternative causes identified by MRI scan overall, the decision to obtain imaging at the time of presentation may be even more straightforward for the nonspecialist, especially in patients who may not report the presence of cancer or systemic disease. There is also a belief that , no meaningful intervention is necessary in acute brainstem stroke although this is unsupported.

In the modern era of medicine, prompt initiation of antiplatelet therapy or anticoagulation for brainstem infarction; and immediate evaluation and control of blood pressure in the setting of hypertensive brainstem hemorrhage represent interventions that are often instituted after neuroimaging identifies such lesions. Some patients with brainstem infarction and isolated third cranial nerve palsies [16], or others with isolated or minimal neurologic deficits [40,41][40,41] have demonstrated cardiac sources of emboli or large vessel thromboembolic disease. Therefore, while small vessel occlusion is one potential cause for a brainstem infarction, the causes of such infarction and their subsequent management may be heterogeneous and different from management of presumed microvascular cranial mononeuropathies. Finally, isolated ocular motor palsies may be a manifestation of multiple sclerosis, and the early initiation of immunomodulatory therapy should be strongly considered in patients with lesions that correlate with dysfunction identified on MRI scan.

It is well known that acute onset sixth nerve palsies can occur due to clival or cavernous sinus lesion and relapsing remitting sixth nerve palsies have been described in the setting of structural skull-based lesions [33 ▪▪ ,34,42][33 ▪▪ ,34,42][33 ▪▪ ,34,42]. In a recent study, nonmicrovascular causes such as structural lesions located in the parasellar or petrous apex were found in patients over the age of 50 years who had remitting relapsing sixth nerve palsy [33▪▪]. The lesions included a structural lesion in five out of the seven patients (71%) three with meningioma and one with malignant melanoma, whereas one had an intracavernous carotid aneurysm. The duration of diplopia in this cohort ranged from 2 weeks to 3 months and interval between episodes ranged from 5 months to 2 years in this study. These patients were initially misdiagnosed as having presumed microvascular, ocular myasthenia, thyroid eye disease and recurrent painful ophthalmoplegic mononeuropathy. Because of the assumption of a benign disorder, further supported by spontaneous resolution, the patients initially did not undergo an MRI of the brain until later in their work up. One patient with meningioma underwent stereo tactic radiosurgery and the patient with aneurysm underwent endovascular treatment.


The advances in the management of multiple sclerosis, stroke and neoplasms make early diagnosis and treatment of these conditions more important than in the past. Although the presence of vasculopathic risk factors in patients at least 50 years of age is a significant predictor for a presumed microvascular cause for an isolated ocular motor mononeuropathy, a substantial proportion of patients with other causes was found in a recent study who also harbored vasculopathic risk factors. The results of this large study suggest that a contrast-enhanced brain MRI likely has an important role to play in the initial evaluation of patients who present with acute-isolated ocular motor mononeuropathies, even in the population over 50 years of age. This is in contrast with other settings when often MRI scans are ordered in patients with unexplained vision loss without visual field defect or optic disc pallor, face pain and headaches where the yield is even lower. It may be reasonable to approach patients with ocular motor cranial mononeuropathy differently depending on which nerve is involved and in the future to determine the yield specifically for each diagnosis. The meaningful yield is the lowest in acute-isolated fourth nerve palsies, but the stakes are high and the results often demanding of action in patients with third and sixth nerve palsy.



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cranial nerve palsy; diplopia; neuroimaging

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