What's Your Diagnosis?

Young patient with long-standing reduced vision

A 29-year-old Asian male presented to UAB Eye Care for periodic ophthalmic evaluation. His history included long-standing poor visual performance. Verbal interaction with the patient was hampered by the fact that he communicated through an interpreter via signing.

It was our understanding that optic atrophy had been diagnosed elsewhere, secondary to nutritional deficits. His medical history substantiated malnutrition during early childhood in the Philippines. By 10 years of age, he and his twin sister suffered from vision loss as well as hearing loss. His mother, who still resides in the Philippines, reported recently to have begun experiencing decreased vision. The patient resides currently with a sponsor in the U.S. He reported that his vision decreased slowly beginning when he was around 10 years old. He also stated that his vision has continued to deteriorate further over the past 10 years.

Fundus photos showing large RNFL defects and temporal optic nerve head pallor in the right and left eyes.
Source: Leo P. Semes, OD

Currently, the patient is treated for depression with 7.5 mg of mirtazapine daily before bedtime. He takes Ocuvite (Bausch + Lomb) eye vitamins daily, which were recommended elsewhere.

OCT of the optic nerve head (ONH) showing temporal nerve fiber layer defects in each eye. The ONH is thin in each temporal cross-section.

Best spectacle-corrected visual acuities were 20/30-1 OD and 20/60-1 OS, not improving with pinhole. Pupil testing revealed round and equally reactive pupils without relative afferent pupillary defect (RAPD). Color vision screening was normal in each eye, and extra-ocular muscle movements were full in each eye. No tropia was observed. Blood pressure was 130/85 mm Hg. Confrontation visual fields were full to 150 degrees in the horizontal meridian. IOPs were 9 mm Hg OD and 10 mm Hg OS by applanation.

Upon pupillary dilation, temporal pallor consistent with nonglaucomatous optic atrophy was observed at each optic nerve head. Distinct retinal nerve fiber layer (RNFL) defects involved the superior and inferior temporal arcuate bundles of each eye encompassing the papillomacular bundle. Cup-to-disc ratios were 0.65/0.60 OD and 0.55/0.60 OS. Lattice retinal degeneration was present in the superior periphery of each eye without high-risk characteristics. OCT findings revealed temporal RNFL thinning consistent with the fundus appearance. Standard automated perimetry was attempted but could not be completed due to the patient’s inability to consistently fixate centrally.

What’s your diagnosis?
See answer on the next page

Young patients presenting with reduced vision and optic atrophy outside the context of recent onset and the apparent absence of corroborating systemic involvement are a diagnostic dilemma. Lack of a consistent history, in this case, further confuses the issue. Both nutritional optic neuropathy (NON) and Leber hereditary optic neuropathy (LHON) have similar clinical characteristics when clinical findings are established. Often a diagnosis of exclusion, NON is an acquired consequence of environmental/external factors that include nutritional deprivation, while LHON has a genetic component. The initial presentation of LHON, however, may be triggered by stressful circumstances such as malnutrition/starvation, alcohol or tobacco use, confusing the diagnosis further especially without a chronological context.

Distinguishing between NON and LHON is an exceedingly challenging distinction in stable presentations. For these reasons, it is important to establish a diagnosis to offer the appropriate management. Dominant optic atrophy (DOA) may be a consideration given the relatively good visual acuity, but the presence of hearing impairment makes this a less likely diagnosis.

Aynsley Girardeau

Nutritional optic neuropathy

This diagnosis is often one of exclusion and is limited by history. An alternative diagnosis besides DOA is LHON. NON results from dietary/nutritional deficits are typically associated with thiamine, folate, vitamin B12 and protein deficiencies. NON is most commonly due to acquired mitochondrial disease, characterized by bilateral symmetrical, painless vision loss accompanied by centrocecal scotomas and varying degrees of associated hearing loss. The insulting lesion may be located in the retina, optic nerve, optic chiasm or optic tracts. Independent of the duration of malnutrition, the onset of symptoms is generally acute, and the maximum vision loss may occur in as few as 24 hours from the onset of visual disturbance, but, more commonly, visual acuities stabilize within 4 weeks following onset. Vision generally improves with early dietary enhancement or nutritional supplementation within several days or weeks, providing that interventions occur early in the disease process. In the absence of intervention, the natural history of the disease results in optic atrophy.

The clinical presentation of NON is virtually indistinguishable regardless of specific nutritional deprivation. Toxic optic neuropathy is a term that includes so-called alcohol and tobacco optic neuropathies and also represents a diagnosis by exclusion. NON is more common in underdeveloped countries and is seen rarely in the U.S. unless associated with certain eating disorders or diets such as veganism. Because NON is a diagnosis of exclusion, hereditary diseases should first be ruled out.

Leber hereditary optic neuropathy

LHON is the best known of all the inherited mitochondrial diseases. Unfortunately, the clinical characteristics of LHON can be similar to those of NON. LHON, however, is an inherited maternal mutation in mitochondrial DNA, and while it may be exacerbated by environmental influences, they did not appear to be a major factor in this case. Phenotypic expression of the disease and visual prognosis depend on the specific genetic mutation. Mitochondria are the powerhouse of the cell and are used for energy production. Theories propose that damage caused by LHON is secondary to oxidative or respiratory strain in the mitochondria.

This process leads to self-directed tissue destruction, or apoptosis, in the RNFL, ganglion cell layer and optic nerve. Vision loss associated with LHON is a multifactorial process including genetic predisposition, as well as other exacerbating factors, such as tobacco use, alcohol consumption, trauma and nutritional deficiencies.

Signs of the acute phase of LHON include reduced visual acuity, cecocentral scotoma, pale optic nerve with hyperemia and microangiopathy of the optic disc. Later the disease progresses to distinct optic atrophy. Color vision deficits have been observed inconsistently. In general, the mean age of onset ranges from 25 to 29 years, but cases of LHON have been reported in patients as young as 1 year and up to 80 (Grzybowski et al.). The onset is rapid and painless, and the time span to stable vision loss is typically short. Visual acuity will likely be worse than 20/200, and recovery is rare. A RAPD is typically absent in both cases because the optic nerve damage is symmetrical bilaterally. LHON is four to five times more common in males in part because estrogen is thought to be protective against the oxidative deficits produced by the diseased mitochondria in LHON.

Current case

Considering the circumstances surrounding the present case, it is reasonable to conclude that LHON is the appropriate diagnosis.

Two interesting findings regarding LHON have been reported recently and may be relevant to this case. First, it has been known for some time that hearing loss can be associated with NON, but now it is suggested that progressive auditory neuropathy may develop with LHON, making this the more likely diagnosis with the hereditary component. The lesion responsible for hearing deficit is thought to be located in the cochlear nerve. Second, a childhood version of LHON has been reported in which the average onset of visual disturbances is before the age of 10 years. LHON cases that manifest earlier tend to have slower visual decline with improved prognosis compared to the traditional form of the disease that manifests between 25 and 29 years of age. Cases of visual recovery with later onset are also more likely. Childhood LHON presents with diffuse optic atrophy without microangiopathy, and those with a slower onset of childhood LHON present with optic atrophy in the temporal region of the optic nerve, consistent with the fundus appearance seen in the present case. Moreover, slowly progressive childhood forms of LHON show less severe vision loss. Many of the characteristics of this case align with slow onset childhood LHON including the visual acuities, which fall within the standard deviation provided. In addition, while the ancestral history and pedigree are circumstantial, the evidence points to LHON.

A thorough history and pedigree are supportive in making a diagnosis of LHON. Visual evoked potential and electroretinogram testing may help distinguish LHON from a retinopathy, and a brainstem evoked auditory potential may further assist in diagnosing an auditory neuropathy. Magnetic resonance imaging may be ordered to rule out compressive lesions of the visual pathway. The absence of apparent hemianopic visual field depressions, although not formally confirmed in the present case, makes a post-chiasmal lesion less likely. Finally, LHON may be confirmed with genetic testing.

Treatment

Treatment for LHON is supportive in nature and, if necessary, includes exams in low vision and occupational therapy. Genetic counseling should be offered to all those who suffer with LHON. Patients should be educated about the importance of a nutrient-rich diet and warned against heavy alcohol consumption and using tobacco products.

Similarly, with NON, instilling proper nutritional habits may prevent further devastation, while genetic counseling and low vision rehabilitation would be indicated as management components for the diagnosis of LHON. Taking these features and factors into account, our diagnosis was LHON. Since the patient was seen, his clinical profile seems to conform to a series reported from Europe.

Current investigations for reversal of LHON have proven less than satisfactory. However, a focus on the spectrum of genotypes combined with OCT investigations suggest that more specific diagnoses may be based on the specific morphology of the photoreceptor layer as well as the presence or absence of microcysts in the inner nuclear layer. Further possibilities for the remediation include mitochondrial replacement therapy and stem cell therapies.

Final diagnosis

In the present case, it is likely that the patient had been misdiagnosed with NON and actually suffers from slow-onset childhood LHON. An apparent positive maternal family history was important for distinguishing between these two diseases. It is believed that the patient and his sister inherited a mitochondrial mutation associated with LHON. A complete pedigree analysis, which was not possible in this case, may have supported the diagnosis. The chronic nutritional deficits that he and his sister reportedly suffered may have exacerbated or accelerated their progressive trajectories.

The patient insists that his vision has progressively decreased in the last 10 years even after having access to enhanced nutritional resources recently. The progressive nature and slow onset of the disease despite good nutrition creates doubt for the diagnosis of NON and also supports the childhood form of LHON. Furthermore, this presumed case of LHON appears to have an associated auditory neuropathy, which has limited documentation previously.

We are currently awaiting results of genetic testing for confirmation of the diagnosis. Our patient has been lost to follow-up, but management recommendations included low vision rehabilitation.

Disclosures: Girardeau and Semes report no relevant financial disclosures.

A 29-year-old Asian male presented to UAB Eye Care for periodic ophthalmic evaluation. His history included long-standing poor visual performance. Verbal interaction with the patient was hampered by the fact that he communicated through an interpreter via signing.

It was our understanding that optic atrophy had been diagnosed elsewhere, secondary to nutritional deficits. His medical history substantiated malnutrition during early childhood in the Philippines. By 10 years of age, he and his twin sister suffered from vision loss as well as hearing loss. His mother, who still resides in the Philippines, reported recently to have begun experiencing decreased vision. The patient resides currently with a sponsor in the U.S. He reported that his vision decreased slowly beginning when he was around 10 years old. He also stated that his vision has continued to deteriorate further over the past 10 years.

Fundus photos showing large RNFL defects and temporal optic nerve head pallor in the right and left eyes.
Source: Leo P. Semes, OD

Currently, the patient is treated for depression with 7.5 mg of mirtazapine daily before bedtime. He takes Ocuvite (Bausch + Lomb) eye vitamins daily, which were recommended elsewhere.

OCT of the optic nerve head (ONH) showing temporal nerve fiber layer defects in each eye. The ONH is thin in each temporal cross-section.

Best spectacle-corrected visual acuities were 20/30-1 OD and 20/60-1 OS, not improving with pinhole. Pupil testing revealed round and equally reactive pupils without relative afferent pupillary defect (RAPD). Color vision screening was normal in each eye, and extra-ocular muscle movements were full in each eye. No tropia was observed. Blood pressure was 130/85 mm Hg. Confrontation visual fields were full to 150 degrees in the horizontal meridian. IOPs were 9 mm Hg OD and 10 mm Hg OS by applanation.

Upon pupillary dilation, temporal pallor consistent with nonglaucomatous optic atrophy was observed at each optic nerve head. Distinct retinal nerve fiber layer (RNFL) defects involved the superior and inferior temporal arcuate bundles of each eye encompassing the papillomacular bundle. Cup-to-disc ratios were 0.65/0.60 OD and 0.55/0.60 OS. Lattice retinal degeneration was present in the superior periphery of each eye without high-risk characteristics. OCT findings revealed temporal RNFL thinning consistent with the fundus appearance. Standard automated perimetry was attempted but could not be completed due to the patient’s inability to consistently fixate centrally.

What’s your diagnosis?
See answer on the next page

PAGE BREAK

Young patients presenting with reduced vision and optic atrophy outside the context of recent onset and the apparent absence of corroborating systemic involvement are a diagnostic dilemma. Lack of a consistent history, in this case, further confuses the issue. Both nutritional optic neuropathy (NON) and Leber hereditary optic neuropathy (LHON) have similar clinical characteristics when clinical findings are established. Often a diagnosis of exclusion, NON is an acquired consequence of environmental/external factors that include nutritional deprivation, while LHON has a genetic component. The initial presentation of LHON, however, may be triggered by stressful circumstances such as malnutrition/starvation, alcohol or tobacco use, confusing the diagnosis further especially without a chronological context.

Distinguishing between NON and LHON is an exceedingly challenging distinction in stable presentations. For these reasons, it is important to establish a diagnosis to offer the appropriate management. Dominant optic atrophy (DOA) may be a consideration given the relatively good visual acuity, but the presence of hearing impairment makes this a less likely diagnosis.

Aynsley Girardeau

Nutritional optic neuropathy

This diagnosis is often one of exclusion and is limited by history. An alternative diagnosis besides DOA is LHON. NON results from dietary/nutritional deficits are typically associated with thiamine, folate, vitamin B12 and protein deficiencies. NON is most commonly due to acquired mitochondrial disease, characterized by bilateral symmetrical, painless vision loss accompanied by centrocecal scotomas and varying degrees of associated hearing loss. The insulting lesion may be located in the retina, optic nerve, optic chiasm or optic tracts. Independent of the duration of malnutrition, the onset of symptoms is generally acute, and the maximum vision loss may occur in as few as 24 hours from the onset of visual disturbance, but, more commonly, visual acuities stabilize within 4 weeks following onset. Vision generally improves with early dietary enhancement or nutritional supplementation within several days or weeks, providing that interventions occur early in the disease process. In the absence of intervention, the natural history of the disease results in optic atrophy.

The clinical presentation of NON is virtually indistinguishable regardless of specific nutritional deprivation. Toxic optic neuropathy is a term that includes so-called alcohol and tobacco optic neuropathies and also represents a diagnosis by exclusion. NON is more common in underdeveloped countries and is seen rarely in the U.S. unless associated with certain eating disorders or diets such as veganism. Because NON is a diagnosis of exclusion, hereditary diseases should first be ruled out.

Leber hereditary optic neuropathy

LHON is the best known of all the inherited mitochondrial diseases. Unfortunately, the clinical characteristics of LHON can be similar to those of NON. LHON, however, is an inherited maternal mutation in mitochondrial DNA, and while it may be exacerbated by environmental influences, they did not appear to be a major factor in this case. Phenotypic expression of the disease and visual prognosis depend on the specific genetic mutation. Mitochondria are the powerhouse of the cell and are used for energy production. Theories propose that damage caused by LHON is secondary to oxidative or respiratory strain in the mitochondria.

PAGE BREAK

This process leads to self-directed tissue destruction, or apoptosis, in the RNFL, ganglion cell layer and optic nerve. Vision loss associated with LHON is a multifactorial process including genetic predisposition, as well as other exacerbating factors, such as tobacco use, alcohol consumption, trauma and nutritional deficiencies.

Signs of the acute phase of LHON include reduced visual acuity, cecocentral scotoma, pale optic nerve with hyperemia and microangiopathy of the optic disc. Later the disease progresses to distinct optic atrophy. Color vision deficits have been observed inconsistently. In general, the mean age of onset ranges from 25 to 29 years, but cases of LHON have been reported in patients as young as 1 year and up to 80 (Grzybowski et al.). The onset is rapid and painless, and the time span to stable vision loss is typically short. Visual acuity will likely be worse than 20/200, and recovery is rare. A RAPD is typically absent in both cases because the optic nerve damage is symmetrical bilaterally. LHON is four to five times more common in males in part because estrogen is thought to be protective against the oxidative deficits produced by the diseased mitochondria in LHON.

Current case

Considering the circumstances surrounding the present case, it is reasonable to conclude that LHON is the appropriate diagnosis.

Two interesting findings regarding LHON have been reported recently and may be relevant to this case. First, it has been known for some time that hearing loss can be associated with NON, but now it is suggested that progressive auditory neuropathy may develop with LHON, making this the more likely diagnosis with the hereditary component. The lesion responsible for hearing deficit is thought to be located in the cochlear nerve. Second, a childhood version of LHON has been reported in which the average onset of visual disturbances is before the age of 10 years. LHON cases that manifest earlier tend to have slower visual decline with improved prognosis compared to the traditional form of the disease that manifests between 25 and 29 years of age. Cases of visual recovery with later onset are also more likely. Childhood LHON presents with diffuse optic atrophy without microangiopathy, and those with a slower onset of childhood LHON present with optic atrophy in the temporal region of the optic nerve, consistent with the fundus appearance seen in the present case. Moreover, slowly progressive childhood forms of LHON show less severe vision loss. Many of the characteristics of this case align with slow onset childhood LHON including the visual acuities, which fall within the standard deviation provided. In addition, while the ancestral history and pedigree are circumstantial, the evidence points to LHON.

PAGE BREAK

A thorough history and pedigree are supportive in making a diagnosis of LHON. Visual evoked potential and electroretinogram testing may help distinguish LHON from a retinopathy, and a brainstem evoked auditory potential may further assist in diagnosing an auditory neuropathy. Magnetic resonance imaging may be ordered to rule out compressive lesions of the visual pathway. The absence of apparent hemianopic visual field depressions, although not formally confirmed in the present case, makes a post-chiasmal lesion less likely. Finally, LHON may be confirmed with genetic testing.

Treatment

Treatment for LHON is supportive in nature and, if necessary, includes exams in low vision and occupational therapy. Genetic counseling should be offered to all those who suffer with LHON. Patients should be educated about the importance of a nutrient-rich diet and warned against heavy alcohol consumption and using tobacco products.

Similarly, with NON, instilling proper nutritional habits may prevent further devastation, while genetic counseling and low vision rehabilitation would be indicated as management components for the diagnosis of LHON. Taking these features and factors into account, our diagnosis was LHON. Since the patient was seen, his clinical profile seems to conform to a series reported from Europe.

Current investigations for reversal of LHON have proven less than satisfactory. However, a focus on the spectrum of genotypes combined with OCT investigations suggest that more specific diagnoses may be based on the specific morphology of the photoreceptor layer as well as the presence or absence of microcysts in the inner nuclear layer. Further possibilities for the remediation include mitochondrial replacement therapy and stem cell therapies.

Final diagnosis

In the present case, it is likely that the patient had been misdiagnosed with NON and actually suffers from slow-onset childhood LHON. An apparent positive maternal family history was important for distinguishing between these two diseases. It is believed that the patient and his sister inherited a mitochondrial mutation associated with LHON. A complete pedigree analysis, which was not possible in this case, may have supported the diagnosis. The chronic nutritional deficits that he and his sister reportedly suffered may have exacerbated or accelerated their progressive trajectories.

PAGE BREAK

The patient insists that his vision has progressively decreased in the last 10 years even after having access to enhanced nutritional resources recently. The progressive nature and slow onset of the disease despite good nutrition creates doubt for the diagnosis of NON and also supports the childhood form of LHON. Furthermore, this presumed case of LHON appears to have an associated auditory neuropathy, which has limited documentation previously.

We are currently awaiting results of genetic testing for confirmation of the diagnosis. Our patient has been lost to follow-up, but management recommendations included low vision rehabilitation.

Disclosures: Girardeau and Semes report no relevant financial disclosures.