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  • 2020–2021 BCSC Basic and Clinical Science Course™

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    5 Neuro-Ophthalmology

    Chapter 7: The Patient With Abnormal Ocular Motility or Diplopia

    Infranuclear Causes of Diplopia

    Intra-axial (fascicular) ocular motor CN palsies are due to lesions of the nerve distal to its nucleus but within the confines of the brainstem. Brainstem lesions tend to affect many structures and therefore produce numerous deficits, allowing accurate topographic localization of the lesion. In the midbrain, intra-axial lesions can damage either CN III or CN IV. Intra-axial involvement of the CN III fascicle can produce 1 of 4 syndromes, each of which includes an ipsilateral CN III palsy:

    1. Damage to the ventral midbrain and the cerebral peduncle can cause a contralateral hemiparesis (Weber syndrome).

    2. Involvement of the red nucleus and substantia nigra may produce contralateral ataxia or tremor (Benedikt syndrome).

    3. Damage to the dorsal midbrain may involve the superior cerebellar peduncle and produce contralateral ataxia (Claude syndrome).

    4. Dorsal lesion with a slightly different configuration can produce the same type of ataxia plus a CN III nuclear lesion and features of supranuclear eye movement dysfunction (Nothnagel syndrome).

    The localization and direct anatomical correlations of these lesions are more important than the eponyms, especially because the use and definitions of these eponyms have varied in the literature.

    As mentioned, involvement of CN IV within the brainstem is uncommon. Pineal tumors may compromise the proximal course of both CNs IV by compressing the tectum of the midbrain. Such lesions may also obstruct the Sylvian aqueduct, leading to elevated intracranial pressure and hydrocephalus, as well as dorsal midbrain syndrome (see Chapter 8).

    Intra-axial lesions of the CN VI nucleus may also injure CN VII, whose fibers curve around the CN VI nucleus at the facial genu (see Chapter 1, Fig 1-36). Intra-axial lesions that involve the CN VI fascicle may also damage the CN VII fascicles, the tractus solitarius, and the descending tract of CN V, resulting in an ipsilateral abduction palsy, facial weakness, loss of taste over the anterior two-thirds of the tongue, and facial hypoesthesia (Foville syndrome). Lesions of the ventral pons can damage CN VI and CN VII along with the corticospinal tract, producing contralateral hemiplegia, ipsilateral facial weakness, and abduction deficit (Millard-Gubler syndrome).

    The subarachnoid segment of the ocular motor CNs extends from the brainstem to the cavernous sinus, where the nerves exit the dura. It is believed that most ischemic CN palsies occur within this section. Ischemic cranial mononeuropathies typically occur in isolation, with maximal deficit at presentation, but occasionally the loss of function progresses over 7–10 days. Pain may or may not be present; if present, it may be quite severe in some patients. Therefore, pain does not distinguish ischemia from aneurysmal compression.

    Ocular misalignment due to ischemic ocular motor CN palsy almost always improves over time, and the diplopia usually resolves within 6 months. Patients require medical evaluation for ischemic risk factors, including diabetes mellitus, hypertensive vascular disease, and elevated serum lipid levels. Progression of ocular misalignment beyond 2 weeks or failure to improve within 3 months is inconsistent with an ischemic cause of a cranial neuropathy and should prompt a thorough evaluation for another etiology. An isolated mononeuropathy of CN III warrants special attention because of the nerve’s close anatomical proximity to the cerebral vasculature (especially the posterior communicating artery) and the potential for aneurysmal compression (discussed later in this chapter).

    Myasthenia gravis may mimic any pattern of painless, pupil-sparing extraocular muscle dysfunction and should be included in the differential diagnosis of such cases. Approximately 10%–15% of patients with giant cell arteritis (GCA) may present with diplopia from a skew deviation, ischemic cranial neuropathy, or extraocular muscle ischemia.

    If the patient has a history of cancer and an ocular motor cranial neuropathy is present, neuroimaging should be performed to rule out a compressive or infiltrative lesion.

    Asbury AK, Aldredge H, Hershberg R, Fisher CM. Oculomotor palsy in diabetes mellitus: a clinico-pathological study. Brain. 1970;93(3):555–566.

    Comer RM, Dawson E, Plant G, Acheson JF, Lee JP. Causes and outcomes for patients presenting with diplopia to an eye casualty department. Eye (Lond). 2007;21(3):413–418.

    Gates P. The rule of 4 of the brainstem: a simplified method for understanding brainstem anatomy and brainstem vascular syndromes for the non-neurologist. Intern Med J. 2005; 35(4):263–266.

    Liu GT, Crenner CW, Logigian EL, Charness ME, Samuels MA. Midbrain syndromes of Benedikt, Claude, and Nothnagel: setting the record straight. Neurology. 1992;42(9):1820–1822.

    Third Cranial Nerve Palsy

    CN III palsies can cause dysfunction of the somatic muscles (superior, inferior, and medial recti; inferior oblique; and levator palpebrae superioris) and the autonomic muscles (pupillary sphincter and ciliary) (Video 7-2). A complete CN III palsy presents with downward and outward deviation of the eye; complete ptosis; and the inability to adduct, infraduct, or supraduct the eye. The pupil may or may not be involved in a complete CN III palsy. Pupillary involvement, which is discussed later in the chapter, is a critical distinction in the setting of a CN III palsy. Partial CN III palsies are more common; they present with variable limitation of supraduction, infraduction, adduction, and variable ptosis with or without pupillary dysfunction (Fig 7-7).

    VIDEO 7-2 Right CN III palsy.

    Courtesy of M. Tariq Bhatti, MD.

    Access all Section 5 videos at www.aao.org/bcscvideo_section05.

    Figure 7-7 Partial CN III palsy. This 62-year-old woman reported experiencing “the worst headache of my life.” A, Examination revealed complete ptosis on the right; a nonreactive, dilated pupil; and severely limited extraocular movement except for abduction. B, Lateral view of a cerebral angiogram demonstrated a posterior communicating artery aneurysm (arrow).

    (Part A courtesy of Steven A. Newman, MD; part B courtesy of Leo Hochhauser, MD.)

    Most isolated unilateral CN III palsies result from (presumed) microvascular injury in the subarachnoid space or cavernous sinus. Less common causes include aneurysmal compression, tumor, inflammation (eg, sarcoidosis), vasculitis, infection (eg, meningitis), infiltration (eg, lymphoma, carcinoma), and trauma.

    Pupil-involving third cranial nerve palsy

    Pupillary dysfunction with CN III palsy results from loss of parasympathetic input and produces a mid-dilated pupil that responds poorly to light. Patients may present with variable dysfunction of the levator palpebrae or extraocular muscles. Aneurysms that arise at the junction of the posterior communicating artery (PCoA) and internal carotid artery (ICA) are juxtaposed to CN III and are, therefore, in a position to produce a CN III palsy as the initial manifestation of aneurysmal expansion or rupture. Pupillary involvement occurs because the pupillomotor fibers reside superficially in the medial aspect of the nerve adjacent to the PCoA (see Chapter 1, Fig 1-31). Thus, until proven otherwise, the clinician must assume that a nontraumatic CN III palsy with pupillary involvement or evidence of progression to pupillary involvement is secondary to an aneurysm. Emergent cerebrovascular imaging (eg, catheter angiography, magnetic resonance angiography [MRA], or computed tomography angiography [CTA], depending on clinical scenario and neuroradiologic consultation) should be undertaken (Fig 7-8). These angiographic methods can detect almost all aneurysms at this location that produce a CN III palsy. Modern CTA and MRA techniques can reliably detect aneurysms as small as 3 mm in diameter. Of these 2 methods, CTA is faster, provides images with slightly greater resolution, and may show evidence of a subarachnoid hemorrhage. Routine magnetic resonance imaging (MRI) acquired with the MRA is more likely to show nonaneurysmal lesions. When neuroimaging appears normal, lumbar puncture may yield evidence of a subarachnoid hemorrhage (xanthochromia of the spinal fluid) or detect an inflammatory or neoplastic cause. Catheter angiography is often used for diagnostic confirmation and definitive treatment of the aneurysm but rarely for diagnosis alone. Although aneurysms are uncommon in patients younger than 20 years, in rare cases they may present as early as the first decade of life.

    Figure 7-8 Computed tomographic angiography (CTA) demonstrates an aneurysm of the left posterior communicating artery. A, Axial and B, coronal views show the aneurysm (white arrows) at the junction of the internal carotid artery (red arrows) and posterior communicating artery (green arrow). The patient presented with a pupil-involving partial left CN III palsy.

    (Courtesy of Prem S. Subramanian, MD, PhD.)

    A patient who presents only with efferent pupillary dysfunction (ie, the pupil is dilated and responds poorly to light) but exhibits normal eyelid and extraocular muscle function almost always has a benign disorder. Such isolated pupillary involvement is not a form of CN III palsy but rather represents a pupil that is either tonic (Adie), pharmacologically dilated, or mechanically damaged (see Chapter 10). Before concluding that the problem is limited to the pupil, the clinician must exclude minor degrees of incomitant strabismus (via careful PACT or Maddox rod testing) in order to exclude a subtle CN III palsy. Tentorial herniation is not a plausible explanation for an isolated, fixed, and dilated pupil in the absence of altered mental status or other neurologic abnormalities.

    Pupillary dysfunction, or a progressive loss of function, does not always indicate the presence of an aneurysm or other serious problem. The vasculopathic form of a CN III palsy may produce some efferent pupillary defect in up to 20% of cases, although the pupillary involvement is generally mild (typically ≤1 mm anisocoria). Elevated fasting blood glucose, hemoglobin A1c, serum lipid levels, or blood pressure indicate an increased probability that microvascular ischemia is the cause of the CN III palsy; however, patients with these risk factors may also harbor aneurysms. Thus, pupillary involvement should prompt neuroimaging in search of an aneurysm.

    Pupil-sparing third cranial nerve palsy

    The term pupil-sparing complete CN III palsy should be reserved for cases in which pupillary function is normal (ie, equal pupil size and reactivity), but there is total loss of eyelid and ocular motor functions of CN III. These are the typical findings for ischemic cranial neuropathy, which usually fully resolves within 6 months. A pupil-sparing complete CN III palsy is almost always benign and secondary to microvascular disease (diabetes mellitus, hypertension, or hyperlipidemia). An acute, isolated, pupil-sparing (but otherwise complete) CN III palsy in a patient over 50 years of age with known vascular risk factors and without history of cancer does not necessarily require neuroimaging. However, a general medical evaluation is indicated to assess the patient’s serum glucose levels, systemic blood pressure, and serum lipid levels. In older adults, screening for vasculitis (eg, GCA) using Westergren sedimentation rate, C-reactive protein, and platelets must also be considered. If progression occurs, other cranial neuropathies develop, or the expected improvement does not ensue within 3 months, then neuroimaging should be undertaken to search for a mass or infiltrative lesion at the base of the skull or within the cavernous sinus. Occasionally, neuroimaging studies need to be repeated to discover a mass, especially if it is within the cavernous sinus. Lumbar puncture may be needed to detect carcinomatous meningitis, inflammation, or infection.

    In contrast, if the pupil-sparing CN III palsy is partial, the pupil reacts normally, with incomplete impairment of levator palpebrae and extraocular muscle function. Although the pupil is normal, this does not have the same benign implication as in pupil-sparing but otherwise complete oculomotor paresis, given that many other fibers within CN III are also “spared.” This distinction is crucial because some partial CN III palsies with normal pupillary function are due to compressive lesions, including aneurysm, and may later progress to involve the pupil (Fig 7-9). An MRA or CTA is therefore indicated to exclude an aneurysm. If the MRA/CTA is negative and the CN III palsy has progressed on follow-up, MRI of the brain and orbits using a gadolinium contrast agent should be obtained to search for an anatomical lesion. As mentioned, if the pupil is involved in any CN III palsy, neuroimaging is indicated.

    The presence of head and periorbital pain is not helpful in establishing the cause of the CN III palsy. Although most CN III palsies caused by aneurysms present with pain, many vasculopathic palsies also produce pain that, in some cases, may be intense.

    Patients with partial CN III palsy secondary to aneurysm tend to have better recovery of function than patients with complete CN III palsy after undergoing the same neurosurgical intervention. Better recovery is also seen in patients with partial CN III palsy versus those with complete CN III palsy resulting from pituitary adenoma or apoplexy.

    Chuang CC, Chen E, Huang YC, Tu PH, Chen YL, Pai PC. Surgical outcome of oculomotor nerve palsy in pituitary adenoma. J Clin Neurosci. 2011;18(11):1463–1468.

    Gu DQ, Luo B, Zhang X, Long XA, Duan CZ. Recovery of posterior communicating artery aneurysm-induced oculomotor nerve paresis after endovascular treatment. Clin Neurol Neurosurg. 2012;114(9):1238–1242.

    Jacobson DM. Relative pupil-sparing third nerve palsy: etiology and clinical variables predictive of a mass. Neurology. 2001;56(6):797–798.

    Jacobson DM, Broste SK. Early progression of ophthalmoplegia in patients with ischemic oculomotor nerve palsies. Arch Ophthalmol. 1995;113(12):1535–1537.

    O’Connor PS, Tredici TJ, Green RP. Pupil-sparing third nerve palsies caused by aneurysm. Am J Ophthalmol. 1983;95(3):395–397.

    Trobe JD. Searching for brain aneurysm in third cranial nerve palsy. J Neuroophthalmol. 2009;29(3):171–173.

    Figure 7-9 Coronal view of CTA demonstrating a large right cavernous internal carotid artery aneurysm (asterisk). The patient initially presented with a pupil-sparing partial right CN III palsy that progressed with subsequent pupillary involvement.

    (Courtesy of Zoë R. Williams, MD.)

    Divisional third cranial nerve palsy

    CN III branches into superior and inferior divisions within the cavernous sinus and superior orbital fissure. Isolated involvement of either division usually indicates a lesion of the anterior cavernous sinus or posterior orbit. The initial diagnostic study of choice is cranial and orbital MRI with contrast and fat suppression in addition to an MRA. If neuroimaging results are normal, then medical evaluation is warranted, including assessment of blood pressure, blood glucose, and serum lipid levels, in addition to Westergren sedimentation rate and C-reactive protein in the appropriate clinical scenario. In rare cases, a divisional CN III palsy may be secondary to brainstem disease, usually from small-vessel stroke (lacunae) or demyelination. Aneurysms are a much less common but potentially lethal cause of divisional CN III palsy. Rare additional causes include tumors, inflammation (eg, sarcoidosis, vasculitis), infection (eg, meningitis), infiltration (eg, carcinomatous meningitis or lymphoma), and trauma.

    Bhatti MT, Eisenschenk S, Roper SN, Guy JR. Superior divisional third cranial nerve paresis: clinical and anatomical observations of 2 unique cases. Arch Neurol. 2006;63(5):771–776.

    Third cranial nerve palsy in younger patients

    Children may experience transient ophthalmoplegia after a viral infection or vaccination. Although aneurysms are rare in children, a pupil-involving CN III palsy necessitates a workup to exclude an aneurysm or other structural etiology. The third edition of The International Classification of Headache Disorders (ICHD) recently introduced recurrent painful oculomotor neuropathy as the new classification for recurrent headaches with subsequent unilateral ophthalmoplegia, replacing the previous term ophthalmoplegic migraine. The recurrent ophthalmoplegia usually presents as a CN III palsy, and onset most often occurs in childhood. Curiously, the ophthalmoplegia develops days after the onset of head pain. MRI may demonstrate reversible thickening and enhancement at the root exit zone of CN III. CN III schwannoma may mimic the fluctuating nature of this condition; however, CN enhancement will persist after resolution of the CN III palsy. Therefore, follow-up MRI is indicated.

    Ambrosetto P, Nicolini F, Zoli M, Cirillo L, Feraco P, Bacci A. Ophthalmoplegic migraine: from questions to answers. Cephalalgia. 2014;34(11):914–919.

    Förderreuther S, Ruscheweyh R. From ophthalmoplegic migraine to cranial neuropathy. Curr Pain Headache Rep. 2015;19(6):21.

    Lyons CJ, Godoy F, ALQahtani E. Cranial nerve palsies in childhood. Eye (Lond). 2015;29(2): 246–251.

    Schumacher-Feero LA, Yoo KW, Solari FM, Biglan AW. Third cranial nerve palsy in children. Am J Ophthalmol. 1999;128(2):216–221.

    Aberrant regeneration of the third cranial nerve

    After nerve axons are damaged, the nerve fibers may regrow to innervate muscles other than those they originally innervated (Fig 7-10). This fiber misrouting produces several synkinetic phenomena (ie, co-contraction of muscles that normally are not activated together). Classic findings include eyelid retraction with adduction or pupillary miosis with elevation, adduction, or depression.

    Figure 7-10 Aberrant regeneration of the right CN III. A, In primary gaze, there is mild ptosis, pupillary mydriasis, and exotropia, all on the right. B, With attempted downward gaze, the right eyelid retracts as fibers of the right CN III supplying the inferior rectus now also innervate the levator muscle.

    (Courtesy of Rod Foroozan, MD.)

    Aberrant regeneration is common after trauma or compression by an aneurysm or tumor but does not occur with microvascular ischemia. Signs of aberrant regeneration without a history of CN III palsy—primary aberrant regeneration—are presumptive evidence of a slowly expanding parasellar lesion, most commonly a meningioma or carotid aneurysm within the cavernous sinus, which requires appropriate neuroimaging.

    Ling JD, Chao D, Al Zubidi N, Lee AG. Big red flags in neuro-ophthalmology. Can J Ophthalmol. 2013;48(1):3–7.

    Excerpted from BCSC 2020-2021 series: Section 5 - Neuro-Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.

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