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2013 The American Academy of Neurology Institute.

VISUAL SYSTEM: OPTIC NERVE AND RETINA

Matthew J. Thurtell, MBBS FRACP

University of IowaIowa City, IA

INTRODUCTION

The optic nerves and/or retina can be involved in a variety of neurodegenerative and genetic diseases. In somecases, the degree of involvement is enough to cause visual symptoms or visual loss that interferes with activitiesof daily living and quality of life. Optic nerve or retinal involvement can also be relatively mild, causing minimal orno symptoms and subtle signs. In such cases, however, identification of optic nerve or retinal involvement can behelpful from a diagnostic perspective.

SYMPTOMS AND SIGNS

Symptoms and signs of optic neuropathyThe cardinal features of an optic neuropathy are decreased central vision (causing decreased visual acuity and/ora central visual field defect), dyschromatopsia (usually red-green), and, when present for more than a few weeks,

optic atrophy. If the patient has a unilateral optic neuropathy or asymmetric optic neuropathies, a relative afferentpupillary defect(RAPD) will also be present. Bedside examination techniques to help identify an optic neuropathyinclude visual acuity testing (e.g., with a near card; use a pinhole if the patient does not have their glasses), colorvision testing (e.g., checking for red desaturation or more sophisticated testing using color plates), confrontationvisual field testing (e.g., using a red colored target to assess for subtle central vision loss), pupil testing (e.g., theswinging flashlight test in low lighting conditions), and ophthalmoscopy. If possible, the patients pupils should bedilated, as subtle optic nerve abnormalities (e.g., temporal disc pallor) can be difficult to identify without seeing theentire optic disc simultaneously.

Symptoms and signs of retinal degenerationRetinal degenerations can cause visual loss that is central and/or peripheral, depending on the distribution of thepathology and retinal elements involved. Degenerations involving the macula and/or cones cause central visionloss and difficulty with vision in bright lighting conditions (hemeralopia). Degenerations involving the peripheral

retina and/or rods cause visual field constriction and difficulty with vision in dim lighting conditions (nyctalopia).Retinal degenerations can also cause dyschromatopsia (usually blue-yellow rather than red-green). Funduscopicabnormalities are typically present, but can be subtle or present only in the periphery of the retina. Thus, a dilatedfunduscopic examination by an Ophthalmologist is essential if retinal degeneration is suspected. Fundus changesthat may be present include vascular attenuation,pigmentary changes (such as bone spicule and salt-and-pepperpigmentation), atrophic changes (such as bulls-eye macular atrophy), and optic atrophy(that sometimes has acharacteristic waxyappearance). Unfortunately, the fundus changes in retinal degenerations are non-specific ingeneral, the fundus changes cannot be relied upon for a definitive diagnosis, although a particular diagnosis mightbe considered likely depending on the associated clinical features.

When it is unclear if a patients central vision loss is due to optic neuropathy or retinal degeneration, it canbe helpful to perform aphotostress recovery testat the bedside.

1The test is performed by first checking the visual

acuity in each eye. With one eye covered, the patient is then instructed to look directly at a bright light source withthe other eye for 10 seconds. The time taken for the patient s vision to recover to within one line of their baselinevisual acuity is recorded. Patients with normal eyes will usually recover within 40 seconds (average is about 25

seconds). Patients with central vision loss due to retinal disease will often take longer than a minute to recover,whereas those with central vision loss due to optic neuropathy will have normal or near-normal recovery times.


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INVESTIGATIONS

Most investigations for suspected optic nerve and retinal disease are not available to the Neurologist and need tobe arranged with the help of an Ophthalmologist or Neuro-Ophthalmologist.

Visual field testingVisual field testing (perimetry) is essential for determining the pattern and severity of visual field loss due to opticnerve or retinal disease.Automated perimetry(e.g., Humphrey or Octopus) evaluates the central 24-30 degrees

of vision and can quantify the degree of visual field loss relative to age-matched normal controls. Most automatedperimetry evaluates the ability of the patient to see static (non-moving) stimuli and relies on the patient being ableto maintain steady fixation on a central visual target, which requires good central vision. Kinetic perimetry(withthe Goldmann or Octopus perimeters) can be used to evaluate for peripheral as well as central vision loss. Kineticperimetry is very helpful in patients with retinal degenerations, where it will demonstrate peripheral visual field loss(e.g., visual field constriction or ring scotomas), and those with severe central visual loss (e.g., due to severe opticneuropathies or maculopathies), in whom static automated perimetry may be of limited diagnostic value or difficultto obtain due to inability to maintain steady central fixation.

Funduscopic imagingPhotographs of the fundus can be useful to identify and document funduscopic findings. Photographs of the opticdisc and macula can be combined with those of the mid- and far-peripheries to create a montage. Certain retinaldegenerative changes (e.g., bulls-eye configuration) can be more prominent on fluorescein angiography. Fundus

autofluorescence allows for the topographical mapping of lipofuscin in the retinal pigment epithelium. Lipofuscin isa fluorescent pigment that accumulates in the retinal pigment epithelial cells as a consequence of photoreceptordegradation and, thus, autofluorescence can be useful for detecting subtle abnormalities in patients with retinaldegenerations.

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Optical coherence tomographyOptical coherence tomography(OCT) is an ophthalmic imaging technique that uses light waves to produce high-resolution cross-sectional images of the optic nerve and retina. Since different structures (e.g., retinal layers) havediffering optical reflectivity, they can be visualized with OCT. Furthermore, the thickness of different layers can becalculated from the images and compared with age-matched normal controls. Measurement of the peripapillaryretinal nerve fiber layer and macular ganglion cell layer thicknesses can be useful for demonstrating axonal loss inpatients with mild optic neuropathies. Measurement of the total macular thickness and thickness of various retinallayers can help in the evaluation of retinal degenerations.

3Abnormalities at the inner-outer segment junction may

be evident on OCT, reflecting photoreceptor layer disruption or degeneration.

ElectrophysiologyElectrophysiology can be helpful for the investigation of visual loss in the setting of neurodegenerative or geneticdisease. Measurement ofvisual-evoked potentials (VEP) is of limited use and can be misleading. For example, alow-amplitude VEP could be misinterpreted as indicating optic neuropathy in a patient who has vision loss due toretinal degeneration. Electroretinography(ERG), however, is essential when a retinal degeneration is suspected.Full-field ERG records the mass response of the retina to flashes of light. Use of different stimuli in differing statesof light adaptation allows for evaluation of the different retinal elements (e.g., cones, rods, etc).

4Since the full-field

ERG records the response of the entire retina to these stimuli, it may not be abnormal in patients with focal retinalpathology (e.g., maculopathy). Multi-focal ERG allows for the topographic evaluation of the ERG responses in themacula and is more sensitive than full-field ERG for detecting macular dysfunction.

5Indeed, the multi-focal ERG

can be grossly abnormal even when funduscopic changes are absent or subtle.

NEURODEGENERATIVE AND GENETIC DISEASES AFFECTING THE OPTIC NERVES

Leber hereditary optic neuropathy (LHON)LHON is caused by point mutations in mitochondrial DNA (mtDNA), with the most frequent causative mutationsbeing at positions 11778 (about 69% of cases), 14484 (about 14% of cases), and 3460 (about 13% of cases) inthe mtDNA; these involve genes encoding subunits of complex 1 of the mitochondrial respiratory chain.

6Most

patients with LHON are male, with onset of symptoms typically occurring during adolescence or early adulthood.The classic presentation is with acute painless central vision loss in one eye; there will be signs of a unilateraloptic neuropathy. Funduscopic examination will reveal mild hyperemic disc edema with peripapillary telangiectatic


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vessels during the acute phase, with subsequent optic atrophy. The fellow eye is involved in almost all patientswithin a year, typically within 8 weeks. Affected patients do not have other neurologic deficits. The prognosis forrecovery of vision is poor and treatment options are limited, although a prospective randomized controlled trial ofidebenone (a coenzyme Q10 analogue) demonstrated that it may improve vision in a portion of patients.

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Dominant optic atrophy (DOA)DOA has an autosomal dominant inheritance and can be caused by a number of different genetic mutations. Themost commonly identified mutations involve the OPA1 gene on the long arm of chromosome 3. However, up to

50% of patients will not have an identifiable mutation in this gene. DOA presents with slowly progressive painlessbinocular central vision loss. The vision loss usually begins in the first decade of life. Often, the patient is unawarethat there is a problem until they are found to have decreased visual acuities or optic atrophy on eye examination.The severity of vision loss is variable, with visual acuities ranging from 20/20 to worse than 20/200. Patients willtypically have dyschromatopsia, but no RAPD (as both optic nerves are equally affected in most cases). Sincefunduscopic examination shows temporal optic disc cupping and temporal pallor, these patients can sometimesbe mistakenly diagnosed with primary open angle glaucoma. Some patients have other neurologic deficits (so-called OPA plus), including sensorineural hearing loss, ataxia, peripheral neuropathy, ataxia, chronic progressiveexternal ophthalmoplegia, and spastic paraparesis.

8At present, there is no treatment known to modify the course

of DOA.

Wolfram syndromeWolfram syndrome is a rare autosomal recessive condition that is characterized by diabetes insipidus, diabetes

mellitus, progressive binocular vision loss with optic atrophy, and sensorineural hearing loss (alternatively knownas DIDMOADsyndrome). Two types are now recognized: type 1 (WF1) is caused by mutations in the WS1 genelocated on the short arm of chromosome 4, and type 2 (WF2) is caused by mutations in the CISD2 gene locatedon the long arm of chromosome 4.

9Patients with WF2 are distinct in having a decreased lifespan without diabetes

insipidus. Patients with Wolfram syndrome can develop a number of other neurologic and ophthalmic signs. Atpresent, there is no treatment known to modify the course of WF1 or WF2.

Behr syndromeBehr syndrome is a rare condition that is characterized by optic atrophy beginning in childhood, pyramidal tractsigns, ataxia, mental retardation, and musculoskeletal deformities, such as pes cavus. Most cases are autosomalrecessive in inheritance, but autosomal dominant inheritance has been described in some families.

Optic neuropathy with hereditary ataxiasOptic nerve involvement is common in Friedreich ataxia.

10However, it is mild in most patients, such that they do

not develop significant vision loss until late in the course of the disease. Occasional patients can acutely developpainless monocular vision loss mimicking LHON.

10Optic atrophy can also be seen in some autosomal dominant

spinocerebellar ataxias (SCAs). The SCAs are defined on the basis of the specific genetic mutation; over 30 typesare now recognized on the basis of unique genetic mutations, mostly triplet repeat expansions. Detailed studies ofvision have not been performed for most of the SCA types, since vision loss is usually not prominent. However, itis well established that SCA7 causes retinal degeneration (discussed below).

11Optic atrophy has been reported

in association with some of the SCAs, including SCA1.12

Retinal nerve fiber layer thinning has been demonstratedon OCT in SCA2 and SCA3, implying subclinical optic nerve involvement.

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Optic neuropathy with hereditary polyneuropathiesOptic neuropathy can be seen in patients with Charcot-Marie-Tooth (CMT) disease, but is typically mild. Opticatrophy and visual loss are prominent features of an X-linked recessive CMT disease variant caused by mutationsin the PRPS1 gene, which encodes an enzyme involved in purine metabolism and nucleotide biosynthesis.

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Optic neuropathy with other inherited neurodegenerative and metabolic diseasesVisual loss due to optic atrophy can occur in a large number of other inherited neurodegenerative and metabolicdiseases, e.g., Krabbe infantile leukodystrophy, Canavan disease, Leigh disease, Pelizaeus-Merzbacher disease,metachromatic leukodystrophy, biotinidase deficiency, and various mucopolysaccharidoses.

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NEURODEGENERATIVE AND GENETIC DISEASES AFFECTING THE RETINA

Retinal changes in Alzheimer diseaseAlthough visual dysfunction inAlzheimer disease is predominantly due to involvement of primary and associationcortex (i.e., in the visual-variantof Alzheimer disease), there has been an interest in identifying retinal biomarkersfor this disease. Macular drusen, extracellular deposits of amyloid-associated proteins, and retinal microvascularchanges are reported to be possibly associated with Alzheimer disease.

16However, many of these abnormalities

are non-specific and have not been demonstrated as specific or sensitive biomarkers of the disease.

Retinal changes in Parkinson diseaseSince patients with Parkinson disease can have afferent visual dysfunction, there has been interest in identifyingretinal abnormalities in this disease. Alterations in ERG latencies and amplitudes have been demonstrated in anumber of studies and structural changes (e.g., swelling of photoreceptors, intracellular inclusions in the outerplexiform layer of the retina, etc) have also been noted.

17However, funduscopic examination is typically normal.

Furthermore, the functional implications of the ERG and structural changes are uncertain.

Retinal degeneration with mitochondrial myopathiesPigmentary retinal degeneration is well established to occur in association with the mitochondrial myopathies, inparticularKearns-Sayre syndrome (which is also characterized by chronic progressive external ophthalmoplegia,cardiac conduction defects, and sensorineural hearing loss). The severity of the visual loss and ERG changes isvariable. Pigmentary retinal degeneration can be seen in association with weakness and ataxia in the so-called

NARP syndrome, which is caused by a mutation at position 8993 of the mtDNA. Pigmentary retinal degenerationcan also be seen in association with other mitochondrial myopathies, including mitochondrial encephalopathy withlactic acidosis and stroke-like episodes (MELAS) and myoclonic epilepsy with ragged red fibers (MERRF).

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Retinal changes with muscular dystrophiesPatients with myotonic dystrophycan have mild degenerative retinal changes, but these are not usually clinicallysignificant.

19Although visual symptoms and retinal degenerative changes are not a feature ofDuchenne muscular

dystrophyorBecker muscular dystrophy, ERG abnormalities can be present depending on the mutation position;these implicate a role for dystrophin in normal retinal physiology.

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Retinal degeneration with hereditary ataxiasRetinal degeneration is a prominent feature of SCA7. Early in SCA7, there is central visual loss, with decreasedvisual acuity and central scotomas, but relative sparing of peripheral vision and night vision. Dyschromatopsia inthe blue-yellow axis might be detected years prior to symptom onset. The retinal degeneration produces granularpigmentary and atrophic changes in the macula, giving a distinctive bulls-eye configuration. However, this fundusappearance is not seen until late in the disease. The fundus may initially look normal or show only subtle changes(e.g., vascular attenuation), even when there is significant central visual loss, thereby delaying diagnosis.

21Full-

field ERG is abnormal once funduscopic changes are apparent, but multi-focal ERG may be more sensitive fordetecting macular dysfunction in the early stages of the disease when there is only central visual loss.

22,23Retinal

degeneration has also been reported in patients with SCA1.24

An autosomal recessive disease characterized byFriedreich-like ataxia and vision loss due to retinitis pigmentosa has been reported with mutations in the a-TTPgene, which is important for vitamin E metabolism.

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Retinal changes with other inherited neurodegenerative and metabolic diseasesRetinal changes can occur in a large number of other inherited neurodegenerative and metabolic diseases. Theinfantile and juvenile forms ofneuronal ceroid lipofuscinosis can cause retinal pigmentary changes in addition toERG changes. In Batten disease, visual loss can be the presenting symptom and there may be a characteristic

bulls-eye appearance to the macula. Retinal degeneration can be seen in the setting of abetalipoproteinemia; theidentification of this disorder is important, as therapy with vitamins A and E can ameliorate the retinal dysfunction.Pigmentary retinal degeneration can also be seen withperoxisomal disorders and mucopolysaccharidoses. Thegangliosidoses, such as Tay-Sachs disease, can give a characteristic cherry-red spoton the fundus examination;this occurs because the retinal ganglion cells surrounding the fovea become filled with ganglioside, giving a gray-white appearance to the retinal nerve fiber layer. A retinopathy can also occur in some amino acid disorders, suchas cystinosis.

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