McGettrick P, Eustace P. The W.E.B.I.N.O. syndrome. Neuro-Ophthalmology. 1985;5:109–115.

Mills DA, Frohman TC, Davis SL, et al. Break in binocular fusion during head turning in MS patients with INO. Neurology. 2008;71(6):458–460.

One-and-a-Half Syndrome

One-and-a-half syndrome combines a horizontal gaze palsy and ipsilateral INO (Fig 8-7). This syndrome is caused by a pontine abnormality that is large enough to involve the MLF and the PPRF (or the sixth nerve nucleus) on the same side of the brainstem. The only horizontal eye movement remaining is abduction of the eye contralateral to the lesion (horizontal eye movements are lost in 1 eye, whereas they are “half” lost in the fellow eye, hence the name); vertical gaze is preserved. A lesion producing the one-and-a-half syndrome but also involving the intra-axial portion of the facial nerve is termed the eight-and-a-half syndrome (7 + 1.5 = 8.5). Stroke is the most common cause of this disorder. Familiarity with brainstem anatomy allows accurate localization of the various syndromic combinations.

Figure 8-7 One-and-a-half syndrome. This 15-year-old patient had a brainstem glioma that caused a gaze palsy to the left (right photograph) and a left internuclear ophthalmoplegia (evident here as incomplete adduction of the left eye on gaze to the right; left photograph). The only horizontal eye movement was abduction of the right eye. (Courtesy of Steven A. Newman,

MD.)

Espinosa PS. Teaching NeuroImage: one-and-a-half syndrome. Neurology. 2008;70(5):e20.

Frohman TC, Galetta S, Fox R, et al. Pearls & Oy-sters: the medial longitudinal fasciculus in ocular motor physiology. Neurology. 2008;70(17):e57–e67.

Infranuclear Causes of Diplopia

Intra-axial (fascicular) ocular motor nerve 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. At the level of the midbrain, intra-axial lesions can damage either the third or fourth nerve. Intra-axial involvement of the fascicle of the third nerve can produce 1 of 4 syndromes, each of which includes an ipsilateral third nerve palsy. Damage to the ventral midbrain and the cerebral peduncle can cause a contralateral hemiparesis (Weber syndrome). Involvement of the red nucleus and substantia nigra may produce contralateral ataxia or tremor (Benedikt syndrome). Damage to the dorsal midbrain may involve the superior cerebellar peduncle and produce contralateral ataxia (Claude syndrome). A dorsal lesion

with a slightly different configuration can produce the same type of ataxia plus a third nerve nuclear lesion and features of supranuclear eye movement dysfunction (Nothnagel syndrome). The localization and direct anatomical correlation of these lesions is more important than the eponym, especially because the use and definitions of these eponyms have varied in the literature.

As mentioned earlier, involvement of the fourth cranial nerve within the brainstem is uncommon. Pineal tumors may compromise the proximal course of both fourth nerves 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 the dorsal midbrain syndrome (see Chapter 7).

Intra-axial lesions of the nucleus of the sixth cranial nerve may also injure the seventh cranial nerve, whose fibers curve around the sixth nerve nucleus at the facial genu (see Chapter 1, Fig 1-38). Intra-axial lesions that involve the fascicle of the sixth nerve may also damage the fascicle of the seventh nerve, the tractus solitarius, and the descending tract of the trigeminal nerve, 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 the sixth and seventh nerves along with the corticospinal tract, which produces contralateral hemiplegia and ipsilateral facial nerve palsy and abduction deficit (Millard-Gubler syndrome).

The subarachnoid segment of the ocular motor nerves extends from the brainstem to the cavernous sinus, where the nerves exit the dura; most ischemic cranial nerve palsies are thought to occur within this section. The diagnosis of ischemic (microvascular or diabetic) ocular motor nerve palsies is one of exclusion. Ischemic cranial mononeuropathies typically occur in isolation and with maximal deficit at presentation; occasionally, the loss of function progresses over 7–10 days. Pain may or may not be present and, if present, may be quite severe in some patients; pain does not distinguish ischemia from more urgent causes.

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

Myasthenia gravis may mimic any pattern of painless, pupil-sparing extraocular motor dysfunction and should be included in the differential diagnosis of such cases.

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Third Nerve Palsy

Third nerve palsies can cause dysfunction of the somatic muscles (superior, inferior, and medial recti;

inferior oblique; and levator palpebrae superioris) and of the autonomic muscles (pupillary sphincter and ciliary). Patients with a complete third nerve palsy present with complete ptosis, with the eye positioned downward and outward and unable to adduct, infraduct, or supraduct, and with a dilated pupil that responds poorly to light (Fig 8-8). Partial third nerve palsies are more common and present with variable limitation of upward, downward, or adducting movements; ptosis; or pupillary dysfunction.

Figure 8-8 Complete third nerve 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 third nerve palsies result from (presumed) microvascular injury in the subarachnoid space or cavernous sinus. Occasionally, isolated third nerve palsies may occur owing to brainstem lesions such as microvascular infarct. Less common causes include aneurysmal compression, tumor, inflammation (eg, sarcoidosis), vasculitis, infection (eg, meningitis), infiltration (eg, lymphoma, carcinoma), and trauma.

Pupil-involving third nerve palsy

Pupillary dysfunction with third nerve palsy results from loss of parasympathetic input, which produces a mid-dilated pupil that responds poorly to light. Patients may present with variable dysfunction of the levator palpebrae or extraocular muscles innervated by the third nerve. Aneurysms that arise at the junction of the posterior communicating artery (PCoA) and internal carotid artery (ICA) are juxtaposed to the third cranial nerve and are, therefore, in a position to produce a third nerve palsy with pupillary involvement as the initial manifestation of an expansion or rupture (see Chapter 1, Fig 1-33).

The pupillomotor fibers of the oculomotor nerve reside superficially in the medial aspect of the nerve adjacent to the PCoA, a common site for aneurysm formation. Thus, a nontraumatic third nerve palsy with pupillary involvement or evidence of progression to pupillary involvement must be assumed to be secondary to an aneurysm until proved otherwise. 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 8-9). Almost all aneurysms at this location producing a third nerve palsy can be detected by these angiographic methods. Modern CTA and MRA can reliably detect aneurysms as small as 3 mm in diameter. Of the 2, CTA is faster, provides 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. Lumbar puncture may yield evidence of a hemorrhage (xanthochromia of the spinal fluid) or detect an inflammatory or neoplastic cause when neuroimaging appears normal. Although aneurysms are uncommon before age 20 years, they may present, rarely, as early as the first decade of life. Catheter angiography is often obtained for diagnostic confirmation and definitive treatment of the aneurysm but rarely for diagnosis alone.

which improves (and usually fully resolves) within 3 months. A complete pupil-sparing third nerve palsy is almost always benign and secondary to microvascular disease, often associated with diabetes mellitus, hypertension, or hyperlipidemia. An acute, isolated, pupil-sparing, but otherwise complete third nerve palsy in a patient over 50 years of age with appropriate vascular risk factors but without history of cancer does not necessarily require neuroimaging. However, a general medical evaluation may be indicated, with attention given to serum glucose levels, systemic blood pressure, serum lipid levels, and Westergren sedimentation rate. If progression occurs, other cranial neuropathies develop, or the expected recovery 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 contained within the cavernous sinus. Lumbar puncture may be needed to detect carcinomatous meningitis, inflammation, or infection.

In contrast, when there is relative pupil-sparing, the pupil may react normally with only minimal impairment of levator palpebrae and extraocular function (partial third nerve palsy). Although the pupil is normal in this scenario, it does not have the same benign implication as the pupil-sparing but otherwise complete oculomotor paresis, given that many other fibers within the third cranial nerve are also “spared.” This distinction is crucial given that some proportion of partial third nerve palsies with normal pupillary function are related to compressive lesions and may later progress to involve the pupil. Because MRI is widely available, highly sensitive for detecting compressive lesions, and poses minimal risk, images of the brain and orbits using a gadolinium contrast agent and with attention to the path of the affected third nerve should be obtained unless serious contraindications exist.

The presence of head and periorbital pain is not helpful in establishing the cause of the third nerve palsy. Although most third nerve palsies caused by aneurysms present with pain, many vasculopathic palsies also produce pain that, in some cases, may be intense. In older adults, vasculitis (eg, giant cell arteritis) must also be considered.

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Divisional third nerve palsy

The third nerve branches into superior and inferior divisions at the superior orbital fissure or within the cavernous sinus. Isolated involvement of either division usually indicates a lesion of the anterior cavernous sinus or possibly the posterior orbit. The initial diagnostic study of choice is orbital MRI with contrast and fat suppression. If neuroimaging results are normal, then medical evaluation is warranted, including assessments of blood pressure, blood sugar level (ie, glucose determination, hemoglobin A1c), serum lipid levels, Westergren sedimentation rate, and C-reactive protein level. Though rare, a divisional third nerve 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 third nerve palsy. Rare additional causes include tumors, inflammation (eg, sarcoidosis, vasculitis), infection (eg, meningitis), infiltration (eg, carcinomatous meningitis or lymphoma), and trauma.