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ACQUIRED MITOCHONDRIA OPTIC NEUROPATHY


Gatot Suhartono, MD
Neuro Ophthalmology Division- Ophthalmology Department
Faculty of Medicine Airlangga University- Dr. Soetomo Hospital
Surabaya
Mitochondria
Mitochondria play a critical role in the generation of metabolic energy
in eukaryotic cells. They are responsible for most of the useful energy derived
from the breakdown of carbohydrates and fatty acids, which is converted to
ATP by the process of oxidative phosphorylation cytosol. (1) (2) (3) (4)
Mitochondria are increasingly recognized as central players in the life
and death of cells and especially of neurons. The energy dependence of
retinal ganglion cells (RGC) and their axons, which form the optic nerve, is
singularly skewed. In fact, while mitochondria are very abundant in the initial,
unmyelinated part of the axons anterior to the lamina cribrosa, their number
suddenly decreases as the myelin sheath begins more posteriorly. The
vascular system also presents different bloodbrain barrier properties anterior
and posterior to the lamina, possibly reflecting the different metabolic needs
of the optic nerve head (unmyelinated) and of the retrobulbar optic nerve
(myelinated). All factors caused anterior visual pathway susceptible to
damage from various toxins. (3) (4)
Mitochondria host numerous metabolic pathways, including for
example amino acid metabolism and fatty acid oxidation, but the functions on
which we will focus here are those of oxidative energy metabolism, the
related production of reactive oxygen species (ROS), and the role played by
mitochondria in promoting and regulating the apoptotic death of the cell. (1)
(4)
Acquired mitochondria optic neuropathy

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All factors that impact the mitochondrial optic oxidative phosphorylation


caused mitochondrial optic neuropathy. There were two type, congenital and
acquired. The toxic and nutritional optic neuropathies are actually acquired
mitochondrial optic neuropathies and may behave in a similar way with
congenital mitochondrial optic neuropathy. The clinical feature is also similar
to the congenital mitochondrial optic neuropathies. (5)
Clinical syndrome of acquired and congenital mitochondria optic
neuropathy characterized by papillomacular bundle damage, central or
cecocentral scotoma, and reduced color vision. Although these problems
have been classified as optic neuropathies, in many of these entities, the
primary lesion has not actually. Both toxic and nutritional factors play a
synergistic role in several of these disorders. (5)

Tobaccoalcohol amblyopia
Tobaccoalcohol

amblyopia

is

condition

characterized

by

papillomacular bundle damage, central or cecocentral scotoma,and reduction


of color vision in a patient who abuses tobacco and alcohol. This typically
occurs after many years of smoking or alcohol abuse. Most patients with this
amblyopia suffer from severe nutritional depletion, and visual improvement in
these patients seems to be related to improved nutrition. The latter, combined
with an improved diet (green leafy vegetables and fruit daily) and vitamin
supplementation, are the mainstay of therapy. This includes institution of
thiamine 100 mg orally twice daily, folate1 mg once a day, and a multivitamin
tablet daily. Injections of hydroxocobalamin have also been successful in
treating patients with tobacco amblyopia, even when smoking continues. Its

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protective effect is believed to be due to the conversion of free cyanide to


cyanocobalamin by hydroxycobalamin, an analog of vitamin B12. (3) (5) (6)
Alcohol, like tobacco, produces its toxic effects through metabolic
means. Chronic exposure typically leads to vitamin B12 or folate deficiency.
Over time, these deficiencies cause accumulations of formic acid. Both formic
acid and cyanide inhibit the electron transport chain and mitochondrial
function,
resulting in disruption of ATP production and ultimately impairing the ATPdependent axonal transport system. (3) (5) (6)

CEON (Cuban epidemic of optic neuropathy)


CEON (Cuban epidemic of optic neuropathy) were epidemic of
nutritional deficiency optic neuropathy affected tens of thousands of severely
malnourished patients in Cuba between 1992 and 1993. These patients all
reported marked weight loss associated with severe deficiencies of protein
and vitamin intake, in particular of Vitamin B12 and folate. The prompt
administration of cyanocobalamin (3 mg) and
folate (250 mg) per day led to a recovery of visual acuity in a significant
number of cases and this and dietary supplementation brought the epidemic
to an end. (3)

Nutritional Optic Neuropathy


Nutritional optic neuropathy can be defined by visual impairment due
to optic nerve damage secondary to nutritional deficiency. Although we are
describing toxic and nutritional optic neuropathies as separate, the two have
many features in common and both may coexist. Nutritional optic neuropathy
occurs mainly due to vitamin deficiency. Deficiency of thiamine (vitamin B1),
cyanocobalamin (vitamin B12), pyridoxine (vitamin B6), niacin (vitamin B3),

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riboflavin (vitamin B2), and/or folic acid have all been implicated. The clinical
presentation and basic pathophysiology are similar to TON. Most often, they
present as a non-specific retrobulbar optic neuropathy. Currently, the
treatment is limited to the intensive use of vitamins with variable results in
individual cases, and to the implementation of preventive measures, when
feasible. (3) (5) (6)
Antibiotic-related optic neuropathies
Optic neuropathy characterized by sudden onset, bilateral loss of
central vision with cecocentral scotoma, prevalent and selective involvement
of the papillomacular bundle and tortuosity of the retinal vessels may be
precipitated by the administration of at least two antibiotics, chloramphenicol
and ethambutol. (3) (5)
Ethambutol causes optic neuropathy in 15% of patients using the
anti-tuberculous medication. The visual symptoms usually start 28 months
after the drug is started. Dyschromatopsia may be the earliest sign of toxicity,
and blue-yellow color changes are the most common. Central scotomas are
the common visual field defect, but bitemporal defects and peripheral field
constriction have also been reported.Pupillary abnormalities can be subtle,
and visual evoked potential may be needed to confirm the diagnosis. Contrast
sensitivity measurement has also been found effective in detecting subclinical
toxicity. International guidelines on prevention and early detection of
ethambutol-induced ocular toxicity have been published. Other than stopping
the drug, no specific treatment is available for the optic neuropathy caused by
ethambutol. Once this is accomplished, many patients will recover, and this
may take weeks to months. However, there are reports that vision may still
decline or fail to recover even when the drug is stopped if damage is severe
enough. (3) (5) (6)

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The exact mechanism of action of ethambutol is unknown; however, it


has been hypothesized that it acts as a chelating agent that disrupts one of
the several metal-containing enzyme systems in the nucleic acid structures of
mycobacteria. Its toxicity involves the same mechanism. Classically
described as dose- and duration-related and reversible on therapy
discontinuation, reversibility of optic neuritis remains controversial. (5)

Toxic optic neuropaties


Methanol causes focal retrolaminar optic nerve delamination. The
chelating properties of ethambutol have been hypothesized to contribute to its
neurotoxicity. It causes a calcium flux into the mitochondria and excitotoxicity.
Intoxication in industrial settings follows absorption across the skin or lung. It
is metabolized by the enzyme alcohol dehydrogenase (ADH) in the liver, via
formaldehyde to formic acid, the latter being responsible for the adverse
effects. (3) (5)
The toxicity develops from a combined effect of the metabolic acidosis
(H+ production) and an intrinsic toxicity of the formate anion itself. Significant
ingestion causes nausea, vomiting, and abdominal pain. The central nervous
system (CNS) effects of methanol resemble those of ethanol although in low
doses it does not have a euphoric effect. Formic acid accumulates within the
optic nerve and causes classic visual symptoms of flashes of light.
Subsequently, this may progress to scotomas and scintillations. Vision loss is
thought to be caused by interruption of mitochondrial function in the optic
nerve, resulting in hyperemia, edema, and optic nerve atrophy. Pupillary
response to light is compromised and,subsequently, is lost. Definitive
diagnosis of methanol toxicity requires a confirmed increase in the serum
methanol level with gas chromatography (>20 mg/dl), but they do not
correlate with the level of toxicity and thus are not a good indicator of

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prognosis. Arterial pH seems to correlate best with formate levels (<7.2 is a


severe intoxication). (3) (5)
Supportive therapy is aimed at initiating airway management,
correcting electrolyte disturbances, and providing adequate hydration. Gastric
lavage is useful only if patient presents within 2 h of ingestion. Treatment
consists of the usage of buffer like sodium bicarbonate to correct metabolic
acidosis and an antidote to inhibit metabolism of methanol to its toxic
metabolite, formic acid. If necessary, hemodialysis
is supplied to further correct the acidosis, and remove bothmethano l and
formate. (3) (5)
Antidote therapy is directed toward delaying methanol metabolism until
it is eliminated from the system either naturally or via dialysis. This can be
achieved by the use of either ethanol or fomepizole. Ethanol, like methanol,
ismetabolized by ADH, and the enzyme has 1020 times higher affinity for
ethanol compared with methanol. Fomepizole is also metabolized by the
same enzyme; it has the advantage that unlike ethanol it does not cause CNS
depression. Ethanol is, therefore, commonly used and is given IV as a
10%solution in 5% dextrose. A loading dose of 0.6 g/kg is givenfollowed by
an intravenous (IV) infusion of 0.070.16g g/kg/h. Intravenous pulse steroids
have also been tried in a
few patients to salvage vision, and the results have been encouraging. The
benefit

has

been

proposed

to

be

due

to

anti-inflammatory

and

immunosuppressant effect of steroids (5)

Pathophysiology
Still unclear, simiar with congenital mitochondria optic neuropathy.
Defect of mitochondria phosphorilation oxidation cause decreased respiratory
chain efficiency,and decreased production of ATP (adenosine tri phosphate)

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this most probably induces also a chronic increase of ROS production,


possibly via destabilized ubisemiquinone radical dismutation (4).
Mitochondria are transported bi-directionally (antero-retrograde) with
the fast component of the axonal transport. Their saltatory movements are
based on motor proteins. Essentially, the microtubule (MT)-based motility is
supported by kinesin for anterograde transport and by dynein for retrograde.
Thus, mitochondrial axonal transport is an ATP-dependent process and
mitochondria are a major source of ATP. It is conceivable that any energy
depletion due to mitochondrial dysfunction has the potential of affecting
axonal transport, including that of mitochondrial transport itself. (4)
Chronic overproduction of ROS may be an even more important
consequence of the pathogenic mutations besides the partially impaired
respiratory function. Studies of demyelination in Multiple Sclerosis (MS), as
well as in other conditions, indicate that olygodendrocytes are particularly
vulnerable to oxidative stress. (4)
This latter finding prompts speculating that late visual recovery
reported in some LHON patients, especially those with the 14484/ND6
mutation, may be due to the remyelination of denuded axons. In some cases,
degenerative features affecting the oligodendrocyte cytoplasmic tongues that
wrap about intact axons have been noted (4)
Oxidative stress due to chronic ROS overproduction, postulated in
LHON, would most probably affect the retrolaminar myelinated portion of the
optic nerve. In this scenario, the capability of specific tissues and cell types to
counteract an increased oxidative stress is intuitively of major relevance in
determining the degree and distribution of the ultimate damage (4)
RGCs apoptotic death has been documented in other pathological
conditions including glaucoma. Apoptotic RGCs death is also seen after optic
nerve axotomy. Interruption of axonal transport has been implicated in all

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these pathological conditions, and the lack of retrograde transport of


neurotrophic factors has been suggested to play a role. However, other
factors have also been considered, including the activation of the surrounding
glial cells (4)
The role of glial cells and their ability to up-regulate nitric oxide
synthase (NOS) when activated, is becoming increasingly relevant in the
cascade of events that may lead to RGCs death, as recently shown in
glaucoma. There is mounting evidence that astrocyte-derived nitric oxide
(NO) can damage the neuronal mitochondrial respiratory chain targeting in
particular complex I via S-nitrosylation as well as inactivate MnSOD through
peroxynitrite-mediated tyrosine nitration. Preliminary immuno-histochemical
studies on optic nerve specimens from a LHON patient indicate increased
nitrotyrosine labelling, and co-localization studies are ongoing to identify the
cell structures targeted by peroxynitrite (4)
In one study the observation of double-membrane-bound inclusions
within the spared RGCs were interpreted as calcified remnants of
mitochondria suggesting a role for calcium in the cell death process. Other
considerations suggest that RGCs die through the apoptotic pathway.(4)

Diagnosis of acquired mitochondrial optic neuropathy


The diagnosis of acquired mitochondrial optic neuropathy is usually
established by a detailed medical history and careful eye examination. An
extensive history may be the best wayto uncover circumstances and
situations that involve toxic neuropathy. Further testing is guided by the
medical history and physical examination; and is performed to elucidate a
specific toxin or nutritional deficiency as a cause of the optic neuropathy.
Examples include blood testing for methanol levels or vitamin B12 levels.
Patients suspected of having a TON should have a complete hemogram, total

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and differential blood cell counts and urinalysis. The blood and urine also may
be screened for specific toxins, especially if exposure to a particular one is
not identified on history. (5)
On the other hand, if a specific intoxicant is suspected, one would try
to identify it or its metabolites in the patients tissues or fluids. A heavy metal
screening (lead, thallium) should be done based on suspicion. Serum B-12
(pernicious anemia) and red cell folate levels (marker of general nutritional
status) should be obtained in any patient with bilateral central scotomas. A
complete ocular examination for evaluating TON should include color vision
and visual field testing.

Neuroimaging in acquired mitochondrial optic neuropathy


Although

imaging

studies

yield

normal

results

in

acquired

mitochondrial optic neuropathy they almost always are indicated, unless one
is absolutely certain of the diagnosis. The most appropriate imaging study is
an magnetic resonance imaging (MRI) of the optic nerves and chiasm with
and without
gadolinium enhancement. If the medical history is atypical or does not clearly
point to a cause, neuroimaging is required to rule out other causes and
confirm the diagnosis.
Management
The first step in managing acquired mitochondrial optic neuropathy, as
with any toxic process, is to remove the offending agent. This may cause
some reversal of the process. Treatment of TON is dictated by the cause of
the disorder. Medical therapy includes vitamin supplementation which is
needed in many patients with toxic neuropathy especially those with tobacco
alcohol amblyopia. Patients with toxic/nutritional optic neuropathy should be
observed initially every 46 weeks and then, depending on

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their recovery, every 612 months.


The patients visual acuity, pupils, optic nerves, color vision, and visual
fields should be assessed at each visit. Vision gradually recovers to normal
over several weeks, though it may take months for full restoration and there is
always the risk of permanent residual vision deficit. Visual acuity usually
recovers before color vision, the reverse of what happens at the onset of the
disease process. Morbidity of these disorders depends on the risk factors, the
underlying etiology, and the duration of symptoms before the institution of
treatment. A patient with advanced optic atrophy is less likely to recover
visual function than a patient who does not have such pathologic changes.
The prognosis is variable and depends upon the nature of the agent, total
exposure prior to removal, and degree of vision loss at the time of diagnosis.

References
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Neuro-Ophthalmology. San Francisco: American Academy of Ophthalmology;
2011. p. 27-37
3. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and
mytochondrial disfunction : genetic and acquired optic neuropathies.
Neurochemistry International. 2002;(40): p. 573-584
4. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a
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Research. 2004; 23: p. 53-89
5. Sharma P, Sharma R. Toxic Optic Neuropathy. Indian Journal
Ophthalmology. 2011; 59: p. 137-141
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6. Phillips PH. Toxic and deficiency optic neuropathies. In: Miller NR,
Newman NJ, editors. Biousse V, Kerrison JB, associate editors. Walsh and
Hoyts Clinical Neuro-ophthalmology. 6th ed. Baltimore, Maryland: Lippincott
Williams and Wilkins; 2005. p. 455-6.

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