Neuro-Ophthalmic Disease Basics:
A Focus on the Afferent Visual System

Accurately diagnosing neuro-ophthalmic disease can be difficult and intimidating. But, don’t panic! Here’s some help.

By Kelly A. Malloy, O.D.

Release Date: June 2008

Expiration Date: June 30, 2009

Goal Statement:

Many optometrists are uncomfortable with cases of neuro-ophthalmic disease. This paper will help you not only become more confident at diagnosing and monitoring neuro-ophthalmic disease of the afferent visual system, but also feel more confident in referring a patient to a neuro-ophthalmic disease specialist.

Faculty/Editorial Board:

Kelly A. Malloy, O.D.

Credit Statement:

This course is COPE qualified for 2 hours of CE credit. COPE ID 22552-NO. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Malloy has no relationships to disclose.

It is not uncommon for optometrists to dislike or feel very uncomfortable with cases related to neuro-ophthalmic disease. Either you fear that you will overlook an important finding and not refer a patient who truly does have neuro-ophthalmic disease, or you are concerned that you will overanalyze a certain symptom and refer a patient for unnecessary consultation or testing.

What you should realize is that you already have all of the required tools to accurately examine and assess a patient who has a neuro-ophthalmic disease.

You are also capable of determining whether the symptoms and clinical findings warrant additional testing or referral to a neuroophthalmologist. However, you may simply need to spend some time sharpening those tools.

This paper will help you not only become more confident at diagnosing and monitoring neuro-ophthalmic disease of the afferent visual system, but also feel more confident in referring a patient to a neuro-ophthalmic disease specialist.

Separating the Afferent and Efferent Visual Systems

To make neuro-ophthalmic disease less overwhelming, we can break it up into categories: conditions that affect the afferent visual system and conditions that affect the efferent visual system.

It is important to make this distinction so that you know which tests to do when checking for a certain disease process. Because of the wealth of information on this topic, we will specifically focus on neuro-ophthalmic disease of the afferent visual system.

The afferent system carries impulses from the eye to the central nervous system, whereas the efferent system carries impulses from the central nervous system to the eye. Therefore, the afferent system deals with optic nerve function. The efferent system is associated with ocular motility issues, ptosis, anisocoria and nystagmus.

Granted, a disease process may affect both systems. However, if you think of the afferent and efferent systems separately, it will be easier for you to determine which tools and tests to employ to make a proper diagnosis.

Nevertheless, when looking for an optic neuropathy, you must know to test all measures of the afferent visual system.

Afferent Visual System

In regard to the afferent visual system, we are dealing primarily with cranial nerve II, the optic nerve. The main tools needed to evaluate optic nerve function are visual acuity, color vision, pupil testing and visual fields. You already use all of these tools on a regular basis; you just need to be sure you’re using them to their maximum capacity.

Color vision. This test should not only be performed on new patients to check for congenital color deficiency, but also on follow-up examinations because it can reveal a significant amount of information about optic nerve function.^1-5

The optic nerve is sensitive to color. If you believe a non-glaucomatous optic neuropathy exists, you must test color vision. If even a small amount of optic nerve damage is present, color vision will often be reduced. By testing color vision, it is also possible to discover an optic neuropathy in an asymptomatic patient. Typically, the Ishihara color plates are an excellent way to test color vision. Test the same number of plates in each eye to check for a relative difference.

Red desaturation. Another way to look for a color vision problem, or dyschromatopsia, is to test for red desaturation. The optic nerve is sensitive to red, so when it is damaged, red-colored objects may appear washed-out or faded. Some patients who have optic neuropathy describe a red color as appearing orange or pink.

To test for red desaturation, cover the patient’s weaker eye (if there is one) and ask him or her what color object you are holding. Typically, a red-topped dilating drop bottle can be used for this test. Then, ask the patient to cover the other eye and describe the color relative to the fellow eye.⁵

Optimally, you should ask the patient to quantify the percentage of red desaturation. For example, if the patient says an object looks 100% red with the stronger eye and 70% red with the weaker eye, record that the patient has a 30% red desaturation in the weaker eye.

A red target may also be helpful in assessing afferent optic nerve function during confrontation visual field testing. You are likely in the habit of testing the visual field to finger counting techniques.⁶This serves well in identifying a fairly large or dense defect because of the large size of the testing stimulus.

However, it is possible that a small defect, or a less dense relative defect, could be overlooked with conventional confrontation field techniques.

The use of a red target is a good way to look for relative areas of field loss within each eye. To do this, have the patient cover one eye and look at your nose. Hold a red cap in one part of the visual field, and ask the patient what color he or she sees. Then, be sure that the patient stays fixated on your nose, and move the red target into all quadrants of the field. Ask him or her to tell you whether the red cap ever becomes washed-out or faded. Typically, in the area of the field defect, the patient describes the red cap as orange, pink, gray or white. In certain cases, the patient may not even see the cap at all.^1,5

Pupil testing (swinging flashlight). Another tool used to assess optic nerve function is pupil testing.^7-10When pertaining to the afferent visual system, you are not assessing the pupil sizes––instead, you are using the swinging flashlight test to monitor for a relative afferent pupillary defect (RAPD).⁷Yes, this is another tool that you use often; but, again, are you using it correctly? Because you cannot go back and reevaluate pupil testing later in the examination, you may want to get into the habit of personally performing pupil testing on all patients prior to dilation.

Proper technique for the swinging flashlight test is important. Use a bright, focused light, such as a transilluminator. A penlight can produce inaccurate results because of dim lighting or the broad focus of the light. In addition, a binocular indirect ophthalmoscopy (BIO) light has a broad focus and can accidentally be directed into both eyes at the same time, which makes the test inaccurate because you are unable to compare the direct and consensual responses to the light.

Checking for a RAPD. To check for a RAPD, shine the light into only one eye at a time; be sure to hold the light source close to the eyes so that the light is bright enough and you do not get the light in both eyes at the same time.⁹Perform this test in a dark room and instruct the patient to fixate on a distant target.

First, assess the response of each pupil to direct light stimulation. Even if only one eye reacts to light (due to the other pupil being pharmacologically dilated or because of posterior synechiae, sphincter tears, etc.), it is possible to check for a RAPD in either eye. You can compare the direct response to the light when it is shined into the one eye versus the consensual response of that same eye when the light is shined into the fellow eye. This is called reverse, or inverse, testing.

Once you have assessed the response to direct light stimulation, conduct the swinging flashlight technique. The object of the swinging flashlight test is to compare the pupillary escape in each eye. If the escape is not equal, there is a RAPD. Only look at the pupil of the eye you are currently shining the light into. Then, you can infer what the pupil is doing when you direct the light into the other eye.

One major pitfall is looking at the size of the pupils, instead of the pupillary escape, as the endpoint. Do not confuse anisocoria with a RAPD—just because one pupil is larger does not necessarily mean that the patient has a RAPD in that eye.¹⁰

Grading a RAPD. Perform the one-second swinging flashlight test first. Direct the transilluminator into one eye for one second, and then quickly move it to the other eye for one second. Repeat this cycle several times. Be sure to move as quickly as possible from one eye to the other in a straight line (not in an arc-like fashion, which delays the light going into the next eye). With the one-second test, you can only assess for a large RAPD (grade 3 or 4).

If there is no large RAPD, the pupils should remain the same size throughout this test because the direct and consensual responses are equal. However, if there is a grade 3 or 4 RAPD, the pupil in the affected eye will dilate every time the light is moved from the better eye into the poorer eye because the consensual response is better than the direct light response.^7-10

If the pupils remain the same size throughout the one-second test, use the three-second swinging flashlight test to detect smaller RAPDs. The technique is the same, except the light stays directed into each eye for three seconds. If no RAPD is present, both pupils will constrict when the light is shined into them, and they will have an equal escape.

However, if a RAPD is present, the escape will occur faster in the eye with the defect. RAPD grading categorizes the degree of variation in optic nerve function between one eye and the other.

Grade 1+ demonstrates normal initial pupil constriction, and is usually identified by a faster pupillary escape in one eye when compared to the other. This small defect can only be detected with the three-second swinging flashlight test.^7-10A grade 2+ defect may not show great initial constriction, but will usually dilate when the light is shined into it. A grade 3+ would immediately dilate when the light is shined into it on the one-second test. A grade 4+ would do the same, but is usually reserved for a blind eye.

A more precise method of grading an RAPD is with the use of neutral density filters, which usually come in 0.3 log unit increments. They are held in front of the eye without the RAPD and moved upward in a stepwise fashion until the RAPD is no longer apparent. The number of log units needed to eliminate the defect is equivalent to the grade of the RAPD. To confirm this measurement, increase the log units until reversal is noted and it appears as if the RAPD is present in the fellow eye. When using denser filters, you may have to look behind them to visualize the pupil.

Measuring a RAPD is important for determining improvement or worsening at follow-up visits. If a RAPD increases, either the optic nerve function in that eye is worsening or optic nerve function in the fellow eye is improving. If the RAPD decreases, however, this could potentially mean that either the optic nerve function in the eye has improved or that the optic nerve function in the fellow eye has worsened.^11-13Examine visual acuity, color vision and visual fields to confirm either improved or worsened optic nerve function.

The swinging flashlight test is a objective measure of an RAPD. However, sometimes, it is also helpful to perform a subjective examination to determine whether it matches your objective assessment. Shine the light into one eye and ask the patient to look directly into the light. Then, shine the light into the other eye, and ask the patient to judge the relative brightness of the light in each eye.¹⁴Similar to the red desaturation test, instruct the patient to consider the brighter light as a default 100% baseline, and then ask him or her to assign a relative percentage based on the appearance of the light in the fellow eye. For example, if the patient says the light is 100% bright O.D. and 60% bright O.S., record a 40% decreased brightness sense in the left eye.

The degree of RAPD measured in log units can also be compared to the automated visual field, and should match the difference in mean deviation, if the field is accurate.^15,16The more pronounced the defect on a visual field, the greater the mean deviation. Divide the difference in mean deviation between the eyes by 10 for an estimate of the expected RAPD in the eye with the larger negative mean deviation.^15,16

A formal visual field test is not only another necessary and useful tool in assessing afferent nerve function, but also a way to confirm the results of pupil testing.

Similarly, pupil testing can be used to get a sense of the accuracy of the visual field.

Assessing the visual field. Always use several different tools when assessing afferent nerve function to get a true sense of optic nerve function. When used together, the tools should complement and confirm all clinical findings. For example, as described above, the visual field mean deviation should confirm the accuracy of the pupil findings, and conversely so. Likewise, the visual field can also be compared to the optic disc appearance. Because the visual field is a quantification of optic nerve function, it should match the appearance of the optic nerve.^1,17

When you assess the visual field, do not make the mistake of looking only for the number of dark spots. You have to look at the location of the defects and determine which of the four nerve fiber bundles are affected. Examine the visual field with respect to the papillomacular, superior arcuate, inferior arcuate or the nasal nerve fiber bundle. Then, look at the corresponding area on the optic disc with a dilated fundus examination to determine if an associated finding confirms your initial results.

On a visual field, the entire nasal field localizes to the arcuate bundles, assuming the defect is only in one eye and is not a homonymous hemianopia. A nasal defect should correspond with a problem where the arcuate fibers insert into the optic disc. Specifically, for an inferior nasal or inferior arcuate defect, examine the superior temporal optic nerve for any abnormalities. Similarly, for a superior nasal or superior arcuate defect, examine the inferior temporal disc for a corresponding abnormality.

If there is an arcuate defect from a glaucomatous process, expect to see vertical elongation of the cupping with either superior or inferior temporal thinning of the neuroretinal rim. In cases of significant glaucoma, you may even see total loss of the rim tissue in these areas. One aspect that you should not see in glaucoma is pallor of any remaining rim tissue. This finding would be inconsistent with glaucoma and should make you suspicious of a non-glaucomatous optic neuropathy process.¹⁷

Make a conscious effort to determine whether the optic disc appearance matches the visual field when checking for neuro-ophthalmic disease. Evidence of large cupping does not automatically imply that it is a glaucomatous process.

Many other causes of non-glaucomatous optic neuropathy can also cause cupping. These cases may be atypical of glaucoma because of the presence of pallor, asymmetry or consistently normal intraocular pressure. These features make glaucoma a diagnosis of exclusion; therefore, it is necessary to rule out other causes of optic neuropathy.¹⁷

Similarly, if a patient has a history of glaucoma, but the field loss is mainly temporal, you must reconsider the diagnosis. This warrants further work-up to rule out a lesion of the suprasellar cistern. The differential diagnosis of a suprasellar lesion includes a pituitary adenoma, a craniopharyngioma (mass of the pituitary stalk) and a meningioma.¹⁸

The area between the blind spot and the macular region (the intersection of the horizontal and vertical meridians on a visual field) correlates with the temporal aspect of the optic disc. If you note a cecocentral scotoma on a visual field, examine the temporal aspect of the optic disc for any abnormalities.

The nasal aspect of the optic disc corresponds with the most temporal portion of the visual field, which is temporal to the blind spot. Examine the nasal area of the disc for any abnormalities if the problem is localized to the optic nerve. Keep in mind that the correlation will differ if the lesion is localized to the optic chiasm or more posteriorly. In that case, the lesions will typically affect the visual field in both eyes.

Of course, it is also possible to have a visual field defect without a corresponding abnormality on the optic disc.

One example of this is a retrobulbar optic neuritis. However, this would most likely occur in a patient with pain on eye movements and acute vision loss. Typically, it takes about one month after sustaining damage to the optic nerve before pallor is evident.¹⁹

When interpreting a visual field, ask the following questions:

Does the field defect respect either the horizontal or vertical meridian?
Defects that do not respect either meridian localize to the outer choroid or the retina. Defects that respect the horizontal meridian localize to the arcuate bundle, such as a nasal step in glaucoma. Defects that respect the vertical meridian localize to the chiasm or more posteriorly. Defects that respect both the horizontal and vertical meridians localize mainly to the occipital lobe.²⁰

Is the defect present in one eye or both eyes?
A unilateral defect localizes anterior to the chiasm in the optic nerve, retina or choroid. Monocular defects affect the papillomacular, arcuate or nasal nerve fiber bundles. A bilateral defect localizes to the optic chiasm or more posteriorly.

It is possible to have a defect from an anterior process affect both eyes; however, these defects should not respect both the horizontal and vertical meridians. In certain instances, such as an arcuate bundle defect, it may respect only the horizontal meridian.

If the defects are binocular, are they on the same or opposite side of the vertical meridian in each eye?
If the defects are on the opposite side in each eye, they may be characteristic of a bitemporal hemianopia.

However, if the observed defects are on the same side in each eye, they are characteristic of a homonymous hemianopia.²¹

If the defects are characteristic of a homonymous hemianopia, are they identical in each eye?
This implies a congruous defect, which will help to localize it more posteriorly in the occipital lobe.

It is important to be able to distinguish an optic nerve issue from a more posterior process. A detailed history is also highly critical in providing useful information regarding the patient’s condition, and is absolutely necessary to determine the differential diagnoses.

Patient History

In assessing optic nerve and afferent nerve function, you must consider patient history—systemic and ocular health—as well as lifestyle habits. Patients may have more than one problem.

For example, if a patient has a history of a right occipital lobe stroke in the past, expect to see a congruous left homonymous hemianopia; however, if you also see dyschromatopsia (reduced color vision) and neuroretinal rim pallor, do not attribute those findings to the same process.^22,23

It is critical to note that the neuroretinal rim is made up of ganglion cell axons, which synapse in the lateral geniculate nucleus (LGN). Therefore, neuroretinal rim pallor, RAPD and dyschromatopsia mainly occur from lesions at or anterior to the LGN.

An optic tract lesion can cause both a subtle RAPD and bow-tie optic atrophy contralateral to the lesion. However, more posterior lesions, such as in the occipital lobe, will not cause pallor, RAPD or reduced color vision. If noted in a patient with an occipital lobe lesion, a further work-up is needed to look for another etiology.

Systemic history. Important aspects of the systemic history include any condition that can contribute to an ischemic, inflammatory or infectious process.

Also, any history of cancer is important. If there is a history of cancer, always consider that a metastatic lesion could be the cause of the clinical presentation.

Additionally, you must establish whether the patient has had a stroke. If so, you need to detect the location of the stroke (by obtaining a copy of the imaging report) to determine if it accounts for any or all aspects of the clinical presentation. If the patient did not have a stroke, further evaluation is needed.
Ocular history. Clearly, ocular history is important in determining the differential diagnoses for an optic neuropathy. Find out if the patient has a history of glaucoma and if his or her intraocular pressure has ever been elevated. Also, note any history of ocular inflammation and/or trauma.

Often, patients may either forget about or deny a history of trauma to their eyes or head. However, on external evaluation, you will note scars or other telltale signs of past trauma or surgery.

Do not assume that an optic neuropathy is a result of past trauma, unless you have substantive proof from previous records or examinations, or other etiologies have been ruled out.²⁴
Lifestyle history. Because substance abuse could be related to the patient’s condition, you want to note his or her history of tobacco, alcohol and drug use.

If the patient has a history of excessive alcohol consumption, he or she may also be at risk for toxic/ nutritional optic neuropathy. Keep in mind that patients who drink heavily tend not to receive adequate nutrition.²⁵

Further Assessing the Optic Neuropathy

When you determine that a patient has an optic neuropathy because of decreased visual acuity, dyschromatopsia, relative afferent pupillary defect, visual field defects, optic disc pallor or asymmetric cupping, it is time to develop differential diagnoses.

If the patient complains of sudden vision loss, certain conditions should come to mind, depending on the patient’s age and systemic history. For example, a young patient complaining of sudden vision loss will more likely have an optic neuritis (ON), whereas a middle-aged person would more likely have nonarteritic anterior ischemic optic neuropathy (NAION).

An older patient with the same complaint would more likely have arteritic anterior ischemic optic neuropathy (AAION) associated with giant cell arteritis (GCA).^26-28 Additional differences among these conditions relate to specific signs and symptoms.

Generally, a patient does not experience pain associated with NAION; however, pain is typically present with both AAION and ON (with eye movements). Other associated symptoms of AAION and GCA can be jaw claudication, scalp tenderness, fatigue, loss of appetite and fever. With ON, you will see either a normal optic disc (retrobulbar optic neuritis) or disc swelling without hemorrhages (papillitis).^26-28

Also, ask about other symptoms of possible multiple sclerosis (MS), such as weakness, numbness, pares-thesias or any other neurologic symptoms. Keep in mind, however, that MS is only one of many etiologies of optic neuritis.

In NAION, look for a “disk-at-risk” appearance in the fellow eye. This is a small, crowded optic disc with little or no cupping that is predisposed to the ischemic process of NAION. Use caution in considering NAION in a patient with large cupping, as this is uncharacteristic of NAION. Edema occurs in all cases of anterior ischemic optic neuropathy, which is usually associated with hemorrhages during the acute phase. This tends to be more of a pallid swelling in AAION, and less pale in NAION. In fact, due to luxury perfusion, the disc may even appear hyperemic in NAION.^29,30

If the patient presents with pallor of the neuroretinal rim, it suggests a longstanding or chronic process. In this case, there are no signs, such as edema or hemorrhages, that could help determine the etiology; therefore, consider any potential cause of optic neuropathy. Remember, traumatic optic neuropathy is a diagnosis of exclusion, and other etiologies need to be considered.

In terms of a non-acute, nonglaucomatous optic neuropathy, consider a structural abnormality, such as a mass. The patient is in need of neuro-imaging to look for either a structural abnormality such as a mass or abnormal enhancement indicating an inflammatory process, or some form of disruption of the blood-brain barrier.

An MRI is not possible if the patient has a pacemaker or defibrillator, cochlear implants, a bullet or other metal in the body, or recent placement of stents. Other contraindications may include excessive weight (more than 350 pounds) and claustrophobia, which may preclude someone from having an MRI in a closed gantry. When looking for optic neuropathy, it is preferable to perform an MRI in a closed gantry due to its fat suppression ability. In most cases, fat suppression of the orbits is not possible in an open MRI, which makes it harder to evaluate for any enhancement of the optic nerve.

The contrast used in MRI is gadolinium, which causes relatively few adverse effects. However, it is now becoming more frequent for facilities to request a blood urea nitrogen (BUN) and creatinine level in patients with diabetes and hypertension to check for kidney problems. If the BUN or creatinine is elevated, use of gadolinium may be contraindicated. This is because of a newly recognized systemic disorder called nephrogenic systemic fibrosis, which can manifest as significant tissue fibrosis in patients with impaired renal function who have been exposed to gadolinium.³¹

If an MRI is contraindicated, a CT scan may be warranted. A CT scan may be contraindicated in children and pregnant women due to radiation exposure. The contrast used in a CT scan is iodine-based, which may cause allergic reactions. This contrast is contraindicated in patients with iodine or shellfish allergies, as well as in patients with kidney problems. Therefore, a BUN and creatinine level are often needed before contrast administration.

A CT scan is better at imaging blood and bone than an MRI and is the test of choice for detecting trauma. However, CT is inferior to MRI for imaging soft tissue, which is why MRI is preferred for optic neuropathy.

Aside from structural abnormalities, other causes of treatable nonglaucomatous optic neuropathy also need to be ruled out. This is mainly done with laboratory testing. Look for infectious, inflammatory or nutritional problems. Order a complete blood count (CBC) with differential on all patients to ensure there is no indication of anemia or other blood disorders.

Lab Tests for Optic Neuropathy

CBC
C-reactive protein
ESR
Platelet count
Lymetiter
ANA with reflex titer
ACE
RPR
FTA-ABS
Vitamin B₁₂
Folic acid
Methylmalonic acid

For inflammatory conditions, order erythrocyte sedimentation rate (ESR) and C-reactive protein. A CBC, ESR, C-reactive protein and platelet count must be performed on patients over the age of 50 when considering the possibility of GCA. Elevated ESR, C-reactive protein, and platelet counts may be consistent with GCA, as may be a reduced hemoglobin level. Elevated platelet count has been linked to a greater risk of vision loss and/or stroke in patients with GCA.^29,30

The angiotensin-converting enzyme (ACE) test is used to look for sarcoid, and antinuclear antibody (ANA) test is done to check for rheumatologic processes.

For infectious processes, perform a Lyme titer, as well as a fluorescent treponemal antibody absorption assay (FTA-ABS) and rapid plasma reagin (RPR) to test for syphilis. For nutritional problems, check folate and vitamin B₁₂levels.

In addition, methylmalonic acid levels may be obtained. If the methylmalonic acid levels are elevated, this could indicate occult vitamin B₁₂deficiency.³²

If the neuro-imaging work-up and laboratory testing do not reveal a cause of the optic neuropathy, the question remains whether additional work-up is warranted. If there is evidence of continued progression of the field defect or worsening of visual acuity, color vision or RAPD, some tests may need to be repeated, or additional tests, such as a lumbar puncture, may be needed.

Put Your Knowledge and Experience to Work

When examining for neuro-ophthalmic disease, the most important tasks for the primary care optometrist are to fully assess the afferent visual system, quickly determine that there is indeed an optic neuropathy, and make appropriate referrals when warranted. Often, it is difficult to determine whether the work-up is comprehensive or if the neuro-imaging was done properly or read correctly. Therefore, these cases may need to be handled by those who specialize in the field of neuro-ophthalmic disease. However, do not underestimate your role in the care of a patient with a neuro-ophthalmic disease process––you have the important task of being the first individual to identify a problem that needs further evaluation.

Dr. Malloy is an associate professor at Pennsylvania College of Optometry and is the director of Neuro-Ophthalmic Disease Service at the Eye Institute.

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