Combined Vertical Gaze Ophthalmoplegia

Combined vertical gaze ophthalmoplegia is defined as paresis of both upward and downward gaze. Vertical gaze ophthalmoplegia is an example of a brainstem syndrome in which the objective physical findings dictate the diagnostic approach to the problem. Symptoms of vertical gaze ophthalmoplegia, when present, are relatively nonspecific and usually occur in patients who have difficulty looking down, as required in reading, eating from a table, and walking down a flight of stairs. In addition, the patient’s report of symptoms may be unobtainable because of mental status changes caused by dysfunction of the reticular formation that lies adjacent to the vertical gaze generator in the rostral midbrain (see Chapter 35).

The neurological examination discloses associated signs of the disorders listed in the differential diagnosis (see Box 19.1) (Graff-Redford et al., 1985). Coma may be associated with reticular system involvement. Long-tract signs and loss of pupillary reflexes are commonly associated. The syndrome of combined vertical gaze ophthalmoplegia is diagnosed when the ocular findings occur in isolation from long-tract signs.

With combined vertical gaze ophthalmoplegia, vertical saccades and pursuit are lost. This gaze limitation may be overcome by the oculocephalic (doll’s head or doll’s eye) maneuver, which tests the vestibulo-ocular reflex (VOR) (see Chapter 35). It is demonstrated by having the patient focus on an object and rotating the patient’s head; a conjugate eye movement in the opposite direction is the expected response with this maneuver. The Bell phenomenon (reflex movement of the eyes up and out in response to forced eye closure) often is absent. Skew deviation (vertical malalignment of the eyes) may occur. Absence of convergence and loss of pupillary reactions to light are common.

The location of the lesion of combined vertical gaze ophthalmoplegia is the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) for loss of vertical pursuit and saccades (Leigh and Zee, 2006). Box 19.1 lists the disorders involving the rostral mesodiencephalic region (for the differential diagnosis) that cause combined vertical gaze ophthalmoplegia (see Chapter 35). The most common causes of isolated combined vertical gaze ophthalmoplegia are stroke and progressive supranuclear palsy (PSP). In cortical-basal ganglionic degeneration, ocular motility findings are similar to those in PSP but are less severe. Whereas the supranuclear vertical gaze ophthalmoplegia may be prominent early in the course of PSP, obvious vertical and horizontal gaze restriction usually is a late finding in cortical-basal ganglionic degeneration (Rottach et al., 1996).

The diagnostic formulation varies with the age of the patient. Isolated combined vertical gaze ophthalmoplegia usually is due to infarction of the rostral dorsal midbrain. When onset is gradual instead of abrupt or if the patient is young, other disorders should be considered (see Box 19.1). In the elderly, PSP (see Chapter 66) is likely if the onset is gradual. PSP can be mimicked by the treatable Whipple disease (Averbuch-Heller et al., 1999). For Whipple disease, the movement disorder, oculomasticatory myorhythmia, is pathognomonic. Laboratory investigations used to evaluate combined vertical gaze ophthalmoplegia include computed tomography (CT) scan or, preferably, magnetic resonance imaging (MRI). Care should be taken not to overlook lesions inferior to the floor of the third ventricle. Lumbar puncture (LP), syphilis serology, erythrocyte sedimentation rate, and an antinuclear antibody test complete the evaluation when the cause is not obvious. Small-bowel biopsy should be considered if Whipple disease is a possible diagnosis. A polymerase chain reaction (PCR) assay of small-bowel biopsy specimen, cerebrospinal fluid (CSF), or other tissues for the 16S ribosomal ribonucleic acid (RNA) gene of Tropheryma whippelii appears to have both sensitivity and specificity for the diagnosis of Whipple disease (Lee, 2002).

Upgaze Paresis (Dorsal Midbrain or Parinaud Syndrome)

Another brainstem syndrome that often occurs without symptoms is the dorsal midbrain syndrome. When symptoms do occur, the patient has difficulty looking up and may have blurry distant vision caused by accommodative spasm.

The tetrad of findings in the dorsal midbrain syndrome are (1) loss of upgaze, which usually is supranuclear (loss of pursuit and saccades with preservation of the VOR); (2) normal to large pupils with light-near dissociation (loss of the light reaction with preservation of pupilloconstriction in response to a near target) or pupillary areflexia; (3) convergence-retraction nystagmus, in which the eyes make convergent and retracting oscillations after an upward saccade; and (4) lid retraction.

The location of the lesion causing the upgaze paresis of the dorsal midbrain syndrome is the posterior commissure and its interstitial nucleus (Leigh and Zee, 2006). The presence of the full syndrome implies a lesion of the dorsal midbrain (including the posterior commissure), a bilateral lesion of the pretectal region, or a large unilateral tegmental lesion.

The differential diagnosis is presented in Box 19.2. Other than the mild upgaze limitation that occurs with age, the most common cause of loss of upgaze is a tumor of the pineal region. The next most common causes are stroke and trauma. The upgaze palsy portion of the syndrome can be mimicked by any of several conditions: double elevator palsy, PSP, orbital causes such as thyroid ophthalmopathy and the bilateral Brown superior oblique tendon sheath syndrome, pseudo–dorsal midbrain syndrome secondary to myasthenia gravis (MG) or Guillain-Barré syndrome, and congenital upgaze limitation. Forced ductions (see Chapter 16) may be performed by grasping anesthetized sclera with forceps and moving the globe through its range of motion. The presence of restriction of movement with forced ductions implies a lesion within the orbit, as distinct from a midbrain lesion.

The diagnostic formulation for the dorsal midbrain syndrome varies with age. In children and adolescents, pineal region tumors usually are the cause. In young and middle-aged adults, the disorder is uncommon, and the cause may be trauma, multiple sclerosis (MS), or arteriovenous malformation (AVM). In the elderly, stroke and PSP are the most common causes.

The laboratory investigation needed to evaluate dorsal midbrain syndrome is MRI. If no tumor is present and an infectious or inflammatory cause is suspected, an LP should be performed.

Downgaze Paresis

Isolated downgaze paresis is uncommon. Symptoms, when they occur, are related to difficulty in reading, eating, and walking down stairs.

Neurological examination reveals loss of downward pursuit and saccades, although occasionally pursuit may be spared. The vertical oculocephalic maneuver may be normal or may disclose gaze limitation. Convergence may be lost, and gaze-evoked upbeat nystagmus may be present on upward gaze. In young patients, forced ductions should be evaluated for evidence of congenital downgaze limitation.

The site of the lesion for isolated downgaze paresis is bilateral involvement of the lateral portions of the riMLF. The main considerations in the differential diagnosis are ischemic stroke, PSP, and Whipple disease. Laboratory investigations to support the clinical diagnosis include CT or preferably MRI. Lesions may be detected in the rostral mesodiencephalic junction inferior to the floor of the third ventricle.

The diagnostic formulation for isolated downgaze limitation is uncomplicated. When acute in onset, this disorder usually is due to ischemic cerebrovascular disease. In an elderly patient with a progressive course, PSP should be considered.

Internuclear Ophthalmoplegia

Internuclear ophthalmoplegia (INO) is characterized by paresis of adduction of one eye, with horizontal nystagmus in the contralateral eye when it is abducted. It is due to a lesion of the MLF ipsilateral to the side of the adduction weakness.

Surprisingly, most patients with INO have no symptoms. The symptoms that may be associated with INO are diplopia, oscillopsia of one of the two images, and blurred vision. When diplopia is present, it is due to medial rectus paresis (horizontal diplopia) or skew deviation (vertical diplopia).

The MLF carries information for vertical pursuit and the vertical VOR. Consequently, other associated findings with MLF lesions are abnormal vertical smooth pursuit and impaired reflex vertical eye movements (doll’s eye maneuver, Bell phenomenon). Voluntary vertical eye movements (pursuit and saccades) are unaffected. Gaze-evoked vertical nystagmus (usually on upgaze) and skew deviation may be present with the higher eye usually present on the side of the lesion. Skew deviation is a pure vertical ocular deviation that is not due to a cranial nerve palsy, orbital lesion, or strabismus but is caused by disturbed supranuclear input to the third and fourth cranial nerve nuclei. It is thought to be due to unilateral damage to the otolith-ocular pathways or the pathways mediating the VOR (Zwergal et al., 2008).

Internuclear ophthalmoplegia, discussed further in Chapter 35, may occur as a false localizing sign. Brainstem compression due to subdural hematoma with transtentorial herniation and cerebellar masses may cause INO. Myasthenia gravis and Guillain-Barré syndrome also may simulate INO.

The diagnostic considerations are many and varied. Examination can differentiate a lesion of the MLF from a partial third cranial nerve palsy, MG, strabismus, or thyroid ophthalmopathy. The common causes of INO are stroke (including vertebral artery dissection) in older age groups and MS in the young. Keane’s series (Keane, 2005) from a large inner-city hospital reveals that approximately one third of INO cases are due to stroke, one third to MS, and one third to other causes. The less common causes include trauma, herniation, infections, tumor, vasculitis, and surgical procedures.

Laboratory investigations that are performed to elucidate the cause include MRI. Thin cuts are often needed to find the lesion when INO is isolated. An edrophonium (Tensilon) test should be performed to evaluate for MG unless there are associated signs of obligatory brainstem dysfunction.

The diagnostic formulation for INO first necessitates accurate localization of the lesion. Limitation of adduction initially is formulated simply as an adduction deficit. It may be due to (1) a lesion of the midbrain or third cranial nerve disrupting innervation, (2) a disorder of the neuromuscular junction (MG), or (3) a lesion directly involving the medial rectus muscle.

Horizontal Gaze Paresis

Although there are no common symptoms of horizontal gaze paresis, this condition seldom occurs in isolation. Patients may complain of inability to see or to look to the side. Because supranuclear gaze pareses are conjugate by definition, diplopia does not occur.

On examination, with unilateral isolated involvement of the paramedian pontine reticular formation (PPRF), loss of ipsilateral saccades and pursuit is evident. However, full horizontal eye movements are demonstrated with the oculocephalic maneuver.

Lesions of the sixth cranial nerve nucleus cause horizontal gaze paresis with inability of the oculocephalic maneuver to overcome the gaze limitation. Although an associated ipsilateral peripheral facial palsy is usually associated from involvement of the fascicle of the seventh cranial nerve coursing over the sixth cranial nerve nucleus, cases of isolated horizontal gaze paresis caused by sixth nerve nuclear lesions have been reported (Miller et al., 2002). With bilateral lesions, loss or limitation of horizontal saccades and (usually) pursuit in both directions is characteristic. Gaze-paretic nystagmus may be present. In the acute phase, transient vertical gaze paresis and vertical nystagmus or upgaze paresis can occur. In the chronic phase, vertical eye movements are full, although nystagmus may be noted on upgaze.

The location of the lesion for horizontal gaze paresis is the frontopontine tract, mesencephalic reticular formation, PPRF, and sixth cranial nerve nucleus. The explanation of gaze palsy occurring with a nuclear lesion is given later in the chapter (see Syndromes Involving Ocular Motor Nuclei).

The diagnostic possibilities are varied. As with other ocular motility disorders, MG may cause gaze limitation that simulates a central nervous system (CNS) lesion. The diagnostic formulation varies with age, rapidity of onset, and associated clinical findings. For patients with an acute onset who are older than 50 years of age, cerebrovascular disease, ischemic or hemorrhagic, is a likely cause. With a subacute onset before the age of 50 years, a diagnosis of MS should be considered. Congenital cases usually are due to Möbius syndrome. Systemic lupus erythematosus (SLE), syphilis, and Wernicke encephalopathy should be considered for any acquired cases.

Laboratory investigations for horizontal gaze paresis should include MRI. If there are no obligatory signs of CNS dysfunction, MG has to be considered.

Global Paralysis of Gaze

The characteristic symptom of global paralysis of gaze is an inability to look voluntarily (saccades and pursuit) in any direction. Global paralysis of gaze rarely occurs in isolation, however, and signs and symptoms of involvement of other local structures usually are present.

The location of the lesion is the frontopontine tract for saccades, and the parieto-occipitopontine tract for pursuit, where they converge at the subthalamic and upper midbrain level (Thurtell and Halmagyi, 2008). The differential diagnosis for total ophthalmoplegia is given in Box 19.3. The common causes for this presentation are diseases outside the CNS, such as Guillain-Barré syndrome, MG, and chronic progressive external ophthalmoplegia (CPEO); for intraaxial lesions, considerations include stroke, Wernicke encephalopathy, and PSP.

The diagnostic formulation usually is concerned with extraaxial (cranial nerve, neuromuscular junction, or muscle) pathology, because isolated complete ophthalmoplegia is rarely caused by a brainstem lesion. Myasthenia gravis (sometimes in combination with thyroid ophthalmopathy), bilateral cavernous sinus metastases (Ebert et al., 2009), and Guillain-Barré syndrome are more likely possibilities if the onset is subacute. If the presentation is long-standing, slowly progressive, and accompanied by eyelid ptosis, the CPEO syndromes, such as Kearns-Sayre syndrome, should be considered. In these extraaxial disorders, oculocephalic reflexes do not overcome the gaze limitations. PSP is a diagnostic possibility in the elderly, whereas Wernicke encephalopathy should be considered in alcoholics and nutritionally deprived patients. Whipple disease also can cause this rare clinical presentation.

Laboratory investigations for patients with global paralysis of gaze should include MRI. An edrophonium test is performed when MG is suspected. When botulism is suspected, electromyography with repetitive stimulation and serum assay for botulinum toxin should be performed.

One-and-a-Half Syndrome

The one-and-a-half syndrome is characterized by a gaze palsy on looking toward the side of the lesion, together with INO on looking away from the lesion. The common symptoms are diplopia, oscillopsia (the illusion that objects or scenes are oscillating), and blurred vision. Associated findings are skew deviation and gaze-evoked nystagmus on upgaze or lateral gaze, and less commonly on downgaze. Acutely, in the primary position there may be exotropia (one eye deviated outward). Other features may include limitation of upgaze, saccadic vertical pursuit, and loss of convergence.

The location of the lesion is the PPRF or sixth cranial nerve nucleus, with extension to involve the internuclear fibers crossing from the contralateral sixth cranial nerve nucleus, which causes the INO. Entities to consider in the differential diagnosis include MS, stroke, AVM, and tumor of the lower pons. A pseudo–one-and-a-half syndrome may occur with MG or Guillain-Barré syndrome. The diagnostic formulation for the one-and-a-half syndrome is similar to that for INO. Before the age of 50 years, the cause usually is MS; after age 50, it usually is cerebrovascular disease.

Appropriate laboratory investigations for the one-and-a-half syndrome are MRI and, if indicated, LP.

Third Cranial Nerve Nucleus

The common manifestations of nuclear third cranial nerve palsies are diplopia and ptosis. The signs present on the side of the lesion are weakness of the inferior and medial recti and the inferior oblique muscles. Upgaze limitation is present in both eyes because the superior rectus subnucleus is contralateral, and the axons cross within the nuclear complex. In addition, ptosis and dilated unreactive pupils may be present on both sides because the levator subnucleus and Edinger-Westphal nuclei are bilaterally represented.

To localize a lesion to the third cranial nerve nucleus, both eyes must have some involvement because of the bilateral representation. The superior rectus and levator of the eyelid, however, are bilaterally represented and thus cannot demonstrate single muscle involvement. In addition, because the medial rectus subnucleus is in the most ventral portion of the nucleus and all of the dorsal subnuclei send axons through it, single muscle involvement of the medial rectus may not be possible. The eyelid levator subnucleus may be spared because it is located at the dorsocaudal periphery of the nuclear complex.