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Chapter 192 – Hereditary, Nutritional, and Toxic Optic Atrophies

Chapter 192 – Hereditary, Nutritional, and Toxic Optic Atrophies










• Leber’s hereditary optic neuropathy, which arises from an inherited point mutation in mitochondrial DNA, manifests in young adulthood as a distinctive heredodegenerative optic neuropathy.

• Nutritional deficiency states, particularly those that involve the vitamins (e.g., B12 or folic acid) and amino acids used in mitochondrial metabolism (e.g., homocysteine or methionine), can result in a stereotypical optic neuropathy, probably by affecting mitochondria on an acquired basis.

• Certain toxins, possibly through interference with mitochondrial metabolism on an acquired basis (e.g., cyanide), may cause a very similar optic neuropathy.



• Fairly symmetrical visual impairments.

• Loss of central visual acuity.

• Dyschromatopsia.

• Centrocecal visual field defects.

• Temporal optic disc pallor.

• Nerve fiber layer loss in the papillomacular bundle.



• Loss of hearing.

• Peripheral neuropathy.





Leber’s hereditary optic neuropathy (LHON) first was described in 1871 as a disease that produced a subacute onset of dyschromatopsia and bilateral loss of visual acuity, primarily in young men. It was thought originally to be inherited as X-linked with partial penetrance.[1] However, in 1988 Wallace and co-workers[2] described the genetics as a point mutation in the mitochondrial DNA (and hence involves maternal inheritance). Three commonly reported point mutations are involved in the pathogenesis of LHON, all three of which affect complex I of the respiratory chain, and the biochemical defect they induce is still under investigation. Both an impairment of energy production and a chronic increase of reactive oxygen species are the potential consequences of the underlying pathogenic mutations leading to optic nerve degeneration. [3] [4] The fundus examination is unusual, because there are characteristic changes in the optic disc and loss of the papillomacular nerve fiber layer.

The peculiar term tobacco–alcohol amblyopia refers to one of the most frequently considered toxic or nutritional deficiencies. Traquair[5] emphasized that heavy drinking and smoking could lead to a slow, progressive, bilateral visual field loss. Tobacco–alcohol amblyopia is now thought to result from the relative roles of cyanide from tobacco and low levels of B12 , brought about by poor nutrition and poor absorption associated with alcohol consumption.[6] Deficiencies of B12 , other B vitamins and, in particular, folic acid are known to result in a similar clinical picture.[7] Furthermore, a number of toxins, such as ethambutol or methanol, injure the optic nerve and produce a clinical picture that is difficult or impossible to differentiate. Indeed, it is one of the fundamental curiosities of these disorders that they, along with LHON, all have such similar and characteristic clinical manifestations.[8] In considering toxic agents that are best known to cause optic neuropathy, it is remarkable that most are known to interfere with oxidative phosphorylation.[9]


It is said that LHON has a prevalence rate as high as 2% of legally blind individuals in Australia and New Zealand.[10] The age of onset is typically in the late twenties, often at a critical stage in the patient’s domestic and professional life. For almost all pedigrees, men are more likely to demonstrate clinical symptoms than women; however, this ratio varies considerably from country to country.[11] [11A]

It cannot be overemphasized that the papillomacular bundle is the main site of the problem, and it eventually becomes atrophic. The pathophysiology of this injury to the papillomacular bundle probably begins with impairments in mitochondria that involve oxidative phosphorylation. The resultant decrease in adenosine 5′-triphosphate (ATP) may compromise axonal transport which, paradoxically, is highly energy dependent. [12] [13] Hence mitochondria, which arise solely in the soma and have a lifespan of only 7–14 days, may not make it to the distal terminals if the efficiency of transport is compromised due to energy depletion. This situation would be particularly problematic in long fibers, such as those of the peripheral nervous system, or in axons of very narrow caliber, those with minimal or no myelin, and those with a rapid rate of firing. These three latter features are all found in retinal ganglion cells of the papillomacular bundle.[9]

Toxic and nutritional deficiency optic neuropathies are fairly uncommon causes of optic neuropathy in the United States and Western Europe. However, a recent epidemic of optic and peripheral neuropathy in Cuba serves to remind that these types of optic neuropathies may be far more common in the third world than is supposed generally.[14] This family of diseases may be relegated to the background until such times as famine, new application of pharmaceuticals, or changes in the workplace lead to nutritional deficiencies or toxic exposures, which in turn lead to the re-emergence of these diseases.

In terms of deficiencies that result in toxic optic neuropathies, probably the most crucial nutrients are vitamins, particularly vitamin B12 (cobalamin), vitamin B1 (thiamin), vitamin B2 (riboflavin), and folic acid. Proteins, in particular those that contain the sulfur amino acids, are probably also crucial for efficient mitochondrial oxidative phosphorylation. Toxins established most clearly as producers of an optic neuropathy include arsacetin, carbon monoxide, clioquinol, cyanide, ethambutol, hexachlorophene, isoniazid, lead, methanol, plasmocid, and triethyl tin.[15] These agents interfere with mitochondrial oxidative phosphorylation.[16] [17] [18] [19] Certain factors, such as impaired renal



function in patients on ethambutol, may increase the risk and severity of the toxic optic neuropathy.

A number of important agents also exist that are less clearly toxic to the optic nerve, such as carbon disulfide, chloramphenicol, pheniprazine, quinine, and thallium. A large number of other toxins, such as carbon tetrachloride, cassava, dapsone, and suramin, are suspected, but not proven, as causes of optic neuropathy.[15]

The clinical picture found in a large number of different toxic optic neuropathies is essentially the same. Furthermore, the central visual loss associated with dyschromatopsia, the centrocecal scotomas, and the selective loss of the papillomacular bundle that characterize most toxic optic neuropathies are also common to nutritional deficiencies such as single or mixed vitamin deficiencies of B12 , B2 , or folic acid. These findings also have been found in malnourished prisoners of war, frequently with an associated peripheral neuropathy. [20]

It may seem peculiar that so many nutritional deficiency and toxic optic neuropathies produce very similar clinical pictures, yet there are common pathways by which these vitamins work and by which many of these toxins interact. Oxidative phosphorylation within the mitochondria involves the process of electron transfer to oxygen at one end and the production of ATP at the other end. Vitamins such as B12 and folic acid are crucial to this process and deficiency therein results in decreased ATP. Similarly, agents such as cyanide or formate (a metabolic product of methanol) block this electron transport. The final common product of these deficiencies and toxins is decreased ATP production by mitochondria within all of the cells of the body and likely the accumulation of reactive oxygen species (ROS). [20A] Compensatory mechanisms may permit most cells in the body, such as muscle cells, to deal with decreased mitochondrial deficiency perhaps via the production of more mitochondria.[21] However, neurons with axons that are very long, very thin, or unmyelinated (such as the papillomacular nerve fiber bundle) are at a great disadvantage.


LHON typically begins with the sudden onset of painless monocular visual loss, which the patient may describe as a blurring of vision but more often as a central dark or gray cloud. This develops first in one eye and then, soon after (days to several weeks), it occurs in similar fashion in the fellow eye. In contradistinction, most patients who have either toxic or nutritional optic neuropathy experience slowly progressive bilateral loss of central vision. Described below are the ocular manifestations that, on the whole, are quite similar for all three syndromes (LHON, nutritional, and toxic optic neuropathies).

The patient initially may describe an inability to read, see traffic signs, or details in the faces of acquaintances. Patients do not complain of pain or positive visual phenomena, such as photopsias.

On examination, patients generally have bilateral impairments of visual acuity that vary from minimal losses (20/25 [6/7.5]) to hand motion vision (for LHON the usual range is 20/100 [6/30]) to finger counting. The visual acuity loss in the two eyes is usually quite symmetrical. Loss of vision to the light perception or no light perception levels is extremely rare. Loss of color vision is usually more profound than the loss of visual acuity. Very early cases may exhibit isolated dyschromatopsia. The hallmark of this disorder is the visual field defect that consists of a centrocecal scotoma that begins nasal to the blind spot and extends to involve fixation on both sides of the vertical meridian ( Fig. 192-1 ). There is usually an area of relative scotoma that forms a bridge between the two islands of absolute scotoma at fixation and at the blind spot. Often a complete loss of the perception of red occurs, and color perimetry demonstrates a much larger elliptical centrocecal scotoma than found with white light. Pupillary reactions are usually normal, even in the early monocular stages of LHON. There are histopathological findings of a relative preservation of the retinotectal pathway in LHON.[22]





Figure 192-1 Humphrey visual field strategies 30–2. A large stimulus V was used. A, Note the centrocecal scotoma that bridges fixation to the blind spot of the right eye. B, In the left eye, the scotoma seems a little more centralized around fixation. It is notable that this patient, who had tobacco–alcohol amblyopia (mixed toxic and nutritional deficiency optic neuropathy), also had relatively small central scotomas but visual acuities of 20/400 (6/120) in each eye.

In early LHON, a peripapillary microangiopathy may occur.[11] Telangiectatic or tortuous blood vessels may be seen around the optic disc, but this occurs transiently and often is missed until involvement of the second eye becomes apparent. In nutritional deficiencies and toxic optic neuropathies, the fundus may appear normal initially. However, a careful examination may reveal nerve fiber layer losses in the papillomacular bundle, sometimes associated with swelling of the nerve fiber layer in the arcuate bundles above and below the denuded area.[23] Later in the course of the disease, the temporal optic disc often appears mildly pale ( Fig. 192-2 ). The mismatch between relatively mild temporal disc pallor and severe depression of visual acuity, visual field, and color vision may lead to the misconception that the patient is malingering.


A carefully history usually provides enough information to make a presumptive diagnosis of LHON. The patient describes the subacute, painless loss of vision monocularly, possibly followed soon after by involvement of the fellow eye. This slight temporal asymmetry and the family history help to differentiate LHON from nutritional deficiencies and toxic optic neuropathies. Most often, LHON manifests in men in their late teens or early twenties. It can be differentiated from toxic and nutritional optic neuropathies by:

• Family history

• Presence of telangiectatic vessels around the optic nerve head during the acute phase



• Likelihood that one eye is affected before the other (not simultaneous occurrence)

• Confirmation by laboratory study of the point mitochondrial DNA mutation





Figure 192-2 Fundus views reveal mild temporal optic disc pallor. A, Right optic disc. B, Left optic disc. More interesting, however, is the loss of the nerve fiber layer in the papillomacular bundle. This patient, who had tobacco–alcohol amblyopia (mixed toxic and nutritional deficiency optic neuropathy), also had visual acuities of 20/400 (6/120) in each eye, which recovered to only 20/100 (6/30) after changes in habit and diet, and vitamin therapy. In this class of optic neuropathies, relatively severely compromised visual acuities and dyschromatopsia often are found with minimal optic disc atrophy.

The history is particularly helpful to differentiate LHON from toxic and nutritional optic neuropathies. Care must be taken to explore all possible oddities in terms of diet and exposures, with an emphasis on particulars that have changed recently. Suspected toxicities can be confirmed through serum and urine analysis. In particular, 24-hour urine collection for heavy metal screening may yield unexpected results. In addition to serum vitamin levels for B1 , B2 , B12 , and folic acid, it is often useful to obtain serum pyruvate levels as well.


The differential diagnosis for toxic and nutritional optic neuropathies includes disorders that cause acute and subacute symmetrical losses in visual acuity and color vision. The similarity between LHON and nutritional deficiency and toxic optic neuropathies has been addressed.

Kjer’s autosomal dominant optic atrophy is confused less often with toxic and nutritional optic neuropathies. An autosomal dominant family history often occurs, and the optic neuropathy occurs much more slowly and progressively in late childhood.

Although less commonly confused with toxic and nutritional optic neuropathies, chiasmal syndromes sometimes need to be ruled out. Pituitary adenomas or other lesions that impact on the optic chiasm generally present with bitemporal visual field loss, but without any significant loss of central acuity or color vision. However, in the early stages, bitemporal field losses may appear similar to centrocecal scotomas. It sometimes may be confusing as to whether the visual field defect crosses the vertical meridian. Fortunately, chiasmal syndromes nearly always result from mass lesions that are visualized easily on standard imaging studies.

Occasionally, optic neuritis may occur bilaterally. Because there can be almost any type of visual field defect in optic neuritis, the clinical picture of bilateral optic neuritis may appear like that of toxic and nutritional optic neuropathies. If the patient has multiple sclerosis, a number of plaques may be picked up on magnetic resonance imaging; furthermore, most patients who have optic neuritis show dramatic recovery of visual acuity.

A recent area of controversy pertains to the possibility that amiodarone may cause an optic neuropathy. Amiodarone, a benzofuran derivative with vasodilatory and antiarrhythmic properties, is used for treating supraventricular and ventricular cardiac arrhythmias.[24] Although it is a potent antiarrhythmic, numerous side effects, ranging from mild to life threatening, have been described.[25] Among the mild side effects, corneal microdeposits are very common. This can even be used to ascertain the therapeutic dosage of the therapy. The keratopathy usually does not cause any serious visual disturbance, but occasionally the patients may complain about flares, halos, and mild photosensitivity[26] ( Chapter 36 ). Dermatitis and gastrointestinal disturbances are among the other few mild side effects, whereas hypothyroidism and hyperthyroidism, peripheral neuropathy, ataxia, bone marrow depression, and pulmonary toxicity are several of the more severe side effects that are attributed to use of amiodarone.[24] [25] [27] [28]

Some reports suggest that patients on amiodarone therapy may also be at risk for developing an amiodarone-induced optic neuropathy which is hard to distinguish from nonarteritic anterior ischemic optic neuropathy (AION). The most compelling evidence for the existence of amiodarone-induced AION is the increased incidence of AION among patients receiving amiodarone therapy (1.79%[29] ). This is much higher than the incidence of AION in the general population aged 50 or older (which is approximately 0.3%[29] ). However, such a comparison fails to consider that patients on amiodarone therapy have cardiac arrhythmias, hypertension, and other potential risk factors for AION.

Others have suggested that amiodarone produces an optic neuropathy that can be distinguished from AION.[30] Purported amiodarone-induced optic neuropathy may be characterized by the insidious onset of bilateral and symmetrical visual loss with slow progression, whereas AION is characterized by an acute, unilateral visual loss that is rarely progressive. Purported amiodarone-induced optic neuropathy causes a protracted disc swelling that tends to stabilize within several months of discontinuation of medication, but AION is characterized by resolution of disc edema over several weeks.[30]

In purported amiodarone-induced optic neuropathy the cup-to-disc ratio is larger than that seen in AION,[29] and these should be bilateral disc edema.

One theoretical mechanism of amiodarone-induced optic neuropathy has been suggested by a primary lipidosis seen ultrastructurally in one human optic nerve.[31] However, the patient in this case had no associated visual loss, and membranous lipid accumulation is nonspecific in the optic nerve.[31] [32] Most case reports suggesting amiodarone as inducing a type of AION failed to establish causality.[33] [34]

Nonetheless, it may be prudent to perform ophthalmological examinations on patients taking amiodarone. If an amiodarone-induced optic neuropathy is entertained seriously, alternative antiarrhythmic therapy may be considered.[30]

Finally, because the nerve and nerve fiber layer changes in LHON and nutritional and toxic optic neuropathies can sometimes



be very subtle, psychogenic visual loss often is considered in the differential diagnosis. Visual evoked potentials may be useful to document the increased latencies seen in organic disease.


Especially in mixed nutritional optic neuropathies, there may be other associated neurological symptoms, such as paresthesias, ataxia, or hearing impairment. However, these are more characteristic of general nutritional deficiencies sometimes found in clusters in equatorial countries and termed tropical amblyopias, and they usually are not described in cases of toxic exposure or single vitamin deficiency. [35] Visual symptoms may be seen in association with paresthesias and dysesthesias, particularly in the legs, in association with ataxia and hearing loss.[36] This has been described in vitamin deficiencies associated with poor diet, compounded by the ingestion of cassava and by elevated levels of cyanide.[37]


Very little is currently published on the histopathology of these optic neuropathies. However, Sadun et al.,[21] [38] [39] as well as Kerrison et al.,[40] provided ultrastructural characterizations of the three mutations in LHON from genetically characterized pedigrees. In addition to severe losses of retinal ganglion cells in the macular area and depletion of the nerve fiber layer, these authors described accumulations of mitochondria in other orbital tissues and electron-dense, membrane-bound calcium inclusions in the remaining retinal ganglion cells.


If the cause of the toxic or deficiency optic neuropathy can be found and treated early (for example, by cessation of smoking and the administration of vitamins in tobacco–alcohol amblyopia), vision generally returns to near normal over several months. However, there often is permanent visual loss in cases of long-standing toxic or nutritional optic neuropathy. Some investigators advocate general nutritional supplementation for any of these optic neuropathies. However, in the absence of a demonstrable deficiency, no good evidence exists that giving B vitamins or folic acid is of any benefit. Nonetheless, it is not uncommon to see cyanocobalamin (vitamin B12 ) given, not only in suspected cases of tobacco–alcohol amblyopia, but for LHON as well. Idebenone, a quinol analog, has been used recently in a few cases of LHON to ameliorate the net ATP synthesis by providing an alternate pathway, as well as scavenging free radicals with the advantage of concentrating readily in the mitochondria. The results were modest.[41] Patients who have already lost vision in one eye from LHON might be candidates for pharmacological manipulation of mitochondrial metabolism to protect the second eye. [9]


In many cases, prompt administration of the deficient nutrient (such as a vitamin) or removal of the toxin (such as ethambutol) results in significant recovery over a period of several weeks, and sometimes months. However, in cases in which the injury is long standing there may be little or no recovery. In LHON, most patients show minimal recovery, although there have been reports of dramatic and late improvements.[42] The worst visual prognosis is for LHON cases that have the 11778 mutation; over 75% become legally blind in both eyes.[11]





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19. Kozak S, Inderlieb CB, Heller K, et al. The role of copper on ethambutol’s antimicrobial action and implications for ethambutol-induced optic neuropathy. Diagn Microbiol Infect Dis. 1998;30:83–7.


20. Cruickshank EK. Painful feet in prisoners-of-war in the Far East. Review of 500 cases. Lancet. 1946;ii:369–72.


20A. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int. 2002 May;40(6):573–84.


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31. Mansour AM, Puklin JE, O’Grady R. Optic nerve ultrastructure following amiodarone therapy. J Clin Neuroophthalmol. 1988;8:231–7.


32. Sadun AA, Bassi C. Optic nerve damage in Alzheimer’s disease. Ophthalmology. 1990;97:1, 9–17.


33. Sadun AA, Dao J. Part two: annual review in neuro-ophthalmology. J Neuroophthalmol. 1994;14(4):234–49.


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38. Sadun AA. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc. 1998;96:881–923.


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One comment on “Chapter 192 – Hereditary, Nutritional, and Toxic Optic Atrophies

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