4 Cranial Nerves III, IV, VI: Ocular Motor Cranial Nerve Disorders
Abstract
This chapter discusses ocular motor cranial nerve disorders (i.e., cranial nerves [CN] III, IV, and VI). Special attention will be given to pertinent patient presentations, suggestions regarding diagnosis and referral, and details regarding overall cost considerations. The evaluation of diplopia in general, however, is beyond the scope of this chapter. The initial evaluation for an ocular motor cranial neuropathy begins with a complete history and physical examination. Patients with a neurologically nonisolated ocular motor cranial neuropathy (e.g., systemic or constitutional symptoms or signs or localizing neurologic signs) should undergo directed laboratory and imaging evaluations. Patients with neurologically isolated ocular motor cranial neuropathy may require directed neuroimaging (e.g., preferably magnetic resonance imaging [MRI] of the brain and orbit with and without gadolinium), but other imaging modalities may be necessary (e.g., computed tomography [CT] scans or orbital ultrasound) for patients who cannot undergo MRI or for whom specific indications exist for alternative imaging (e.g., thyroid eye disease, sinus disease). Other screening laboratory studies or additional diagnostic modalities (e.g., positron emission tomography [PET] scan or CT of other areas of the body, e.g., chest, abdomen, and pelvis) may be necessary to look for alternative diagnoses (e.g., sarcoid, lymphoma) or sources for potential diagnostic biopsy. The estimated costs for some of these diagnostic tests and procedures are described in the text.
4.1 General Considerations
4.1.1 Diplopia
Diplopia, defined as double vision or the simultaneous perception of two relatively displaced images, is one of the most common symptoms for which patients may seek ophthalmic care. Diplopia can be monocular or binocular: binocular diplopia disappears with the occlusion of one eye, while monocular diplopia persists. Monocular diplopia typically stems from optical and ocular causes such as glasses, contact lenses, cataracts, and corneal disease, while binocular diplopia is more often associated with brain, nerve, or muscle pathologies. 1 In general, the evaluation of monocular diplopia is limited to optical corrections and does not require additional laboratory testing or neuroimaging.
It is important to distinguish paretic etiologies of diplopia, which can be neurogenic in nature, from restrictive etiologies of diplopia involving some mechanical obstruction of the extraocular muscles (EOMs). This chapter is primarily concerned with ocular motor dysfunction resulting from neurogenic (i.e., ocular motor cranial neuropathy) paresis, although some important restrictive etiologies are also discussed.
Oculomotor disorders may be broadly categorized as conditions of the supranuclear, nuclear, or infranuclear regions. Supranuclear disorders involve any structure upstream of the cranial nerve nucleus (CNN), including the cerebral cortex and subcortex. Nuclear disorders are the result of lesions to the CNN in the brainstem. Infranuclear disorders include diseases of the peripheral cranial nerves (CNs) themselves, in addition to disease affecting the neuromuscular junction or muscles. This chapter is primarily concerned with nuclear and infranuclear disorders.
4.1.2 Cranial Nerve III, IV, and VI Palsy
The classical presentation of each CN palsy in isolation will be reviewed. In a CN III (oculomotor nerve) palsy, the affected eye can be deviated downward (hypotropia) and outward (exotropia); this can be accompanied by partial or complete ptosis and possibly pupillary dilation (anisocoria). In a CN IV (trochlear nerve) palsy, the affected eye may be extorted with a small-angle ipsilateral hypertropia (HT). Patients with CN IV palsy will classically develop a worsening HT in contralateral gaze and ipsilateral head tilt. The patient may tilt their head away from the affected side so as to correct this misalignment. In a CN VI (abducens nerve) palsy, the affected eye may be deviated inward (esotropia) and can demonstrate a partial or complete abduction deficit (▶Fig. 4.1, ▶Fig. 4.2 and ▶Fig. 4.3). 1 The most common etiologies of these neurologically isolated ocular motor cranial neuropathies are ischemic small vessel infarcts. Compressive lesions including intracranial aneurysm (predominantly posterior communicating artery aneurysm producing a pupil-involved CN III palsy), trauma (predominantly CN IV but also CN VI), and neoplasm (one or more CNs may be involved) can produce ocular motor CN-related diplopia. Even in the post-neuroimaging era, over a quarter of isolated ocular motor cranial neuropathies remain “idiopathic” in origin. 1 The most common etiologies for ocular motor cranial neuropathy will be discussed in more detail later. Also, please refer to section 3.1, Initial Evaluation and General Considerations. ▶Table 4.1. summarizes estimated costs for some diagnostic tests and procedures that may be indicated in the workup of ocular motor cranial palsy.
Test (CPT code) | Cost: Medicare allowables ($) |
Brain MRI (70553) | 400 |
Head MRA with and without dye (70546) | 510 |
Head CT with and without contrast (70470) | 201 |
CT cerebral angiography (73706) | 375 |
MRI orbit with and without contrast (70543) | 460 |
Orbital ultrasound (76510) | 150 per eye |
Lumbar puncture (62270) | 180 |
Cerebral angiography (36224) | 2,200 |
4.2 Vascular
4.2.1 Stroke
Etiology and Pathophysiology
Stroke is an acute injury to the brain caused by either ischemia or hemorrhage. Ischemic strokes can be further divided by etiology into thrombosis, embolism, thromboembolism, and systemic hypoperfusion. 2 Depending on the location of the stroke, patients may present with very specific CN findings as described below. 1
Presenting Symptoms and Signs
The presenting symptoms and signs of a stroke largely depend on the location of the pathology, which may include the cortex, the brainstem, or the peripheral nerve:
Cortical stroke affecting the frontal eye field regions may result in gaze palsies causing the eye to deviate toward the source of the lesion. 3
Brainstem lesions affecting the midbrain may lead CN III or CN IV nuclear or fascicular palsy, while pontine lesions may present with CN VI palsy. Concurrent neurological deficits based on the location of the lesions may occur.
Peripheral ocular motor cranial mononeuropathies are commonly accepted to be caused by microvascular ischemia. Specific clinical symptoms depend on the nerve affected. Some of the common etiologies, such as diabetic neuropathy, are discussed in greater detail in the following sections. 4
Clinical Decisions
Diagnosis
Diagnosis of an acute cortical or brainstem stroke includes stabilization of vital signs, especially blood pressure, breathing, and body temperature. A noncontrast CT is typically ordered, which is highly sensitive for hemorrhage detection. If a subarachnoid hemorrhage (SAH) is suspected but not present on CT, a lumbar puncture (LP) may be ordered. MRI with and without contrast can also be considered. Consultation with neurology is often requested to assist with the diagnosis. 5
Current Treatment
Although an eyepatch may be worn for symptomatic relief of diplopia, the main concern is differentiating small vessel ischemic, neurologically isolated CN palsy from brainstem infarct. The brainstem stroke is typically defined by other neurologic symptoms and signs that localize to the brainstem (i.e., “the company it keeps”). Typically, diplopia caused by small vessel ischemic strokes is expected to improve over time. Brainstem infarction, however, has a variable prognosis depending on severity and etiology (e.g., hemorrhage). Treatment for the different types of stroke depends on the etiology of the stroke. In general, admission to the hospital and emergent consultation with neurologists, neurosurgeons, interventionalists, and intensivists are often considered based on time of symptoms onset of a brainstem infarct.
4.2.2 Aneurysm
Etiology and Pathophysiology
One of the most common causes of an acute, neurologically isolated CN III palsy is due to compression by an expanding aneurysm, typically of the posterior communicating artery. 6 These aneurysms are at risk of rupturing, resulting in SAH within hours or days of initial onset of symptoms. 7
Presenting Symptoms and Signs
Patients with SAH may present with the worst headache of their life, ptosis, and ophthalmoplegia. The pupil of the affected eye may be dilated. 6
Clinical Decisions
Diagnosis
In general, patients with an acute, painful, CN III palsy with or without pupil involvement should undergo a CT head without contrast emergently. A contrast CTA should be performed in the acute setting in cases where aneurysm is suspected. In patients with an unexplained nonaneurysmal CN III palsy, cranial MRI and MRA may still be necessary despite negative CT/CTA to exclude nonaneurysmal causes of CN III palsy. Patients with a high suspicion for aneurysm, despite a negative CT/CTA and MRI/MRA, may still require standard catheter angiography. 6
Current Treatment
Patients with acute symptomatic aneurysms causing a CN III palsy should be admitted to the hospital. Surgical clipping and endovascular coiling are commonly used techniques for treatment of aneurysms. 8 Diplopia and ptosis may variably recover over time after treatment. If diplopia or ptosis are persistent, prisms or strabismus surgery and/or ptosis repair may be employed. 7
4.2.3 Cavernous Sinus Fistula
Etiology and Pathophysiology
Carotid-cavernous fistula (CCF) occurs when an abnormal connection is formed between the arteries (e.g., internal or external carotid artery) and the cavernous sinus (refer to ▶Fig. 4.4 for anatomy of the cavernous sinus). These connections can appear spontaneously (typically low-flow dural CCF) or may result from head trauma (typically high-flow direct CCF). 9
Presenting Symptoms and Signs
CCF may present with a multitude of symptoms such as vision loss (optic neuropathy, retinal vein occlusion, ocular ischemic syndrome, or glaucoma), exophthalmos, conjunctival congestion and chemosis, and ophthalmoplegia (from CN or EOM dysfunction). CCF can also produce intracranial bleeding. 9 Other findings may include subjective bruit, diplopia, tearing, red eye, ptosis, sensation of ocular foreign body, blurred vision, and headache (▶Fig. 4.5). 10
Clinical Decisions
Diagnosis
Both CT/CTA and MR/MRA have modest sensitivities and specificities for CCF. 10 Imaging of the orbit may show an enlarged superior ophthalmic vein. However, standard catheter angiogram is typically required both for diagnosis and for treatment (endovascular) of CCF.
Current Treatment
Options for dural CCF treatment include observation for spontaneous improvement (in low-flow CCF) and symptomatic treatment with intraocular pressure-lowering agents and endovascular intervention with closure of the CCF. 10 Observation may be the preferred approach to treatment of low-risk, low-flow CCF cases, as up to 70% of dural CCFs will spontaneously close. 10 Endovascular interventional techniques have replaced open surgical procedures as the preferred treatment for direct CCFs, offering a 90 to 100% cure rate with some rare complications.
4.3 Infectious
4.3.1 Herpes Zoster, Syphilis, Lyme Disease, and HIV
Etiology and Pathophysiology
Although relatively uncommon, infectious etiologic agents can cause diplopia from ocular motor cranial neuropathy. These include herpes zoster ophthalmicus (HZO), Lyme disease, neurosyphilis, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS).
Herpes zoster is caused by the reactivation of varicella zoster infection from childhood. In 20% of cases, the disease manifests in CN V along the ophthalmic division and is called HZO. 11 The nerve most commonly affected is CN III, followed by CN VI and then CN IV. Typically the elderly tend to be more affected and the disease is typically self-limiting when immunocompetent. 12 The etiology is usually obvious because of the presence of the cutaneous V1 distribution vesicular rash, but some cases have no rash (herpes zoster sine herpete) or may have vesicles in the distribution of CN VII in the posterior auricular area or palate (Ramsay–Hunt syndrome).
Lyme disease is an infectious disease caused by the spirochete Borrelia burgdorferi resulting in systemic inflammation. Neuropathy of the CNs may be present in the second stage of the disease most commonly affecting CN V but also affecting CN III to CN VI, CN VII, and CN VIII. 13 The diagnosis is usually suggested by seasonal exposure or travel to an endemic area for Lyme disease and a tick bite, the presence of a rash (e.g., target lesion of erythema chronicum migrans), and other symptoms or signs of Lyme disease.
Neurosyphilis is caused by infection by the spirochete Treponema pallidum and can present with central nervous system (CNS) involvement with CN involvement and ocular findings. 14 CN II, CN VI, CN VII, and CN VIII can be commonly affected. 15
HIV/AIDS is caused by the HIV ribonucleic acid (RNA) retrovirus and may result in neuro-ophthalmic side effects either by direct effect of the virus or by indirect effects of opportunistic infections and malignancies as the immune state of the patient declines. Between 50 and 75% of patients with HIV will present with ocular findings. The abducens nerve is most frequently affected, but CN III and CN IV can also be affected. Infections and malignancies most likely to result in neuro-ophthalmic pathologies include syphilis, cryptococcosis, and lymphoma. 16
Presenting Symptoms and Signs
Vertical, horizontal, or oblique diplopia may occur depending on the affected nerve(s) as well as headaches and meningismus among other symptoms. 15 , 17 Patients with HZO may present with Hutchinson’s sign (involvement of the tip of the nose from nasociliary nerve) and unilateral vesicular dermatitis in the ophthalmic division of the trigeminal nerve prior to the development of ophthalmoplegia (▶Fig. 4.6). 11
Clinical Decisions
Diagnosis
Serologic testing for the above culprits may be considered. MRI of the brain with and without contrast may help rule out other causes of CN palsies. 11 , 17 , 18 LP may be considered to test for both opening pressure etiologic agents. 17
Current Treatment
Any patient who is immunocompromised or pregnant with a single or multiple cranial neuropathies due to infection should be considered for admission to the hospital.
Treatment for typical HZO usually consists of oral acyclovir with or without corticosteroids; however, when HZO involves any CNs, intravenous (IV) acyclovir and IV corticosteroids are often recommended. 11 , 19 Treatment for Lyme disease with neurological involvement typically includes IV antibiotics such as ceftriaxone. 17 Treatment for neurosyphilis is IV penicillin G. 18 Treatment for HIV-induced ophthalmoplegia is highly variable depending on the cause. Aside from antiviral therapy given for HIV, it may be beneficial to consult infectious disease, neurology, in addition to ophthalmology to optimize management. 16
Cost considerations | |
Not recommended | – |
Recommended | MRI head and spine with and without contrast |
Practice option | LP and oncology |
4.4 Neoplastic
4.4.1 Leptomeningeal Carcinomatous
Etiology and Pathophysiology
Leptomeningeal carcinomatosis is an uncommon complication of cancer that occurs when the disease metastasizes to the leptomeninges. The terminal condition typically has poor prognosis, with overall survival of approximately 6 to 8 weeks without treatment. 20 It may be present in 5 to 15% of patients with lymphomas or leukemia and in 1 to 5% of solid tumor patients, where most cases are associated with adenocarcinoma. Breast cancer represents the most common primary tumor source of leptomeningeal carcinomatosis, followed by lung carcinoma and melanoma. 21
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