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Woman experiences decreased vision with normal fundus exam

The right and left nerves showed peripapillary telangiectasias. There was bilateral ganglion cell loss and overall mild RNFL thickening with mild temporal thinning.

A 26-year-old female nursing school graduate was referred to the New England Eye Center for decreased vision in both eyes with a normal fundus exam. One month before referral, she noted gradually worsening vision more significant in the right eye than the left. Other than a vague history of back pain and numbness in her right toe, she had no other significant medical or family history. A recent MRI of the brain showed no abnormality.

Examination

The patient’s best corrected visual acuity was 20/200 in the right eye and 20/30 in the left. Pupillary exam showed a trace relative afferent defect on the right. IOPs and anterior segment exam were unremarkable. Funduscopic exam showed peripapillary telangiectasias (Figures 1 and 2). OCT of the ganglion cell layer showed bilateral thinning (Figure 3), while OCT of the retinal nerve fiber layer showed overall mild thickening with mild temporal thinning (Figure 4). After examination, we requested her visual fields from the referring ophthalmologist, which showed bilateral cecocentral scotomas (Figure 5).

Figure 1. Color fundus photographs showing peripapillary telangiectasias.

Images: Dunbar KE, Hedges TR

Figure 2. Red-free photographs of the right and left nerves, respectively, showing peripapillary telangiectasias.
Figure 3. OCT of the ganglion cell layer showing bilateral ganglion cell loss.
Figure 4. OCT of the retinal nerve fiber layer showing mild bilateral thickening with mild temporal thinning.
Figure 5. 24-2 Humphrey visual fields of the right and left eyes showing cecocentral scotomas of the right eye worse than the left.

What is your diagnosis?

Decreased vision

The diagnosis of optic neuropathy can be complex. Therefore, it is important to get a comprehensive history to rule out all potential causes. The differential diagnosis includes mitochondrial optic neuropathy, traumatic optic neuropathy, compressive optic neuropathy, optic neuritis, infiltrative optic neuropathy and ischemic optic neuropathy.

Our patient had no history of trauma, ruling out a traumatic optic neuropathy. Her age, lack of risk factors and bilateral cecocentral scotomas ruled out ischemic optic neuropathy. Optic neuritis, infiltrative optic neuropathy and compressive optic neuropathy were unlikely given a normal MRI of the brain and spine. Consequently, the focus was placed on mitochondrial optic neuropathy. Genetic testing returned positive for LHON 11778 G to A mutation consistent with Leber’s hereditary optic neuropathy.

Discussion

Mitochondrial optic neuropathies can be broken up into hereditary and acquired causes. Hereditary causes include Leber’s hereditary optic neuropathy (LHON), autosomal dominant optic atrophy, Behr’s syndrome and familial dysautonomia. Acquired causes include toxic optic neuropathy (eg, methanol), drug-induced optic neuropathy (eg, ethambutol) and nutritional deficiency (associated with tobacco and alcohol abuse). A thorough history is critical to help narrow the list of differential diagnoses, and prompt diagnosis is important to prevent further damage from any nutritional deficiencies or toxic causes.

LHON is a mitochondrial inherited disease occurring most frequently in males between the ages of 10 and 30 years old. LHON is characterized by significant, abrupt, sequential, painless vision loss. Typically, initial vision loss is monocular followed by abrupt visual loss in the fellow eye. It can be quite devastating. Most frequently, visual acuities are measured worse than 20/200. Cecocentral visual field defects and decreased contrast sensitivity and color vision (most commonly on the red-green axis) are other common characteristics.

LHON has a characteristic triad to help hasten the diagnosis. However, many never exhibit these characteristic signs even at the time of profound vision loss, often making this a challenging diagnosis. This triad includes circumpapillary telangiectatic microangiopathy, pseudoedema of the nerve fiber layer around the disc, and absence of papillary leakage on fluorescein angiography. Imaging often shows ganglion cell complex thinning as well as papillomacular retinal nerve fiber layer (RNFL) thickening lasting for weeks, later followed by temporal RNFL thinning. In several cases, generalized RNFL thinning is also seen. Electrophysiology (PVEP and PERG) is also abnormal.

Given the devastating visual loss, a great deal of research has been conducted, looking into potential treatments and cures for LHON. Idebenone, a member of the quinone family, has shown some promise based on several small case studies. Recently, a larger 24-week multicenter masked randomized placebo-controlled trial was performed. The study included 85 LHON patients with 11778, 3460 and 14484 mutations who were given idebenone 900 mg/day. Results showed no statistical significance in visual acuity recovery, although the authors noted possible improvement in color contrast sensitivity and increase of RNFL thickness. Most importantly, the study showed idebenone was well tolerated without significant side effects.

Other studies have evaluated the protective effect of estrogen. One study showed in vitro cell lines with LHON mutations develop less apoptosis in the presence of estrogen. Other potential neuroprotective free radical scavengers including coenzyme Q (CoQ) analogues and EPI-743 are in early stages of investigation.

Finally, some of the most promising treatments lie with gene therapy. While still early in the process, animal studies with rats have demonstrated safe allotopic delivery of the normal human ND4 subunit gene into the vitreous cavity of the LHON animal model eye, which the authors found may prevent retinal ganglion cell loss. These results give some hope that human therapy for LHON is not far behind.

Further research is focusing on which patients would benefit most from gene therapy. Lam and colleagues found that OCT RNFL thickness averages 72 µm for up to 32 months after visual loss, but drops to an average of 47 µm in patients presenting after 32 months. This could suggest up to a 3-year window after initial visual loss in which to restore some visual function.

A 26-year-old female nursing school graduate was referred to the New England Eye Center for decreased vision in both eyes with a normal fundus exam. One month before referral, she noted gradually worsening vision more significant in the right eye than the left. Other than a vague history of back pain and numbness in her right toe, she had no other significant medical or family history. A recent MRI of the brain showed no abnormality.

Examination

The patient’s best corrected visual acuity was 20/200 in the right eye and 20/30 in the left. Pupillary exam showed a trace relative afferent defect on the right. IOPs and anterior segment exam were unremarkable. Funduscopic exam showed peripapillary telangiectasias (Figures 1 and 2). OCT of the ganglion cell layer showed bilateral thinning (Figure 3), while OCT of the retinal nerve fiber layer showed overall mild thickening with mild temporal thinning (Figure 4). After examination, we requested her visual fields from the referring ophthalmologist, which showed bilateral cecocentral scotomas (Figure 5).

Figure 1. Color fundus photographs showing peripapillary telangiectasias.

Images: Dunbar KE, Hedges TR

Figure 2. Red-free photographs of the right and left nerves, respectively, showing peripapillary telangiectasias.
Figure 3. OCT of the ganglion cell layer showing bilateral ganglion cell loss.
Figure 4. OCT of the retinal nerve fiber layer showing mild bilateral thickening with mild temporal thinning.
Figure 5. 24-2 Humphrey visual fields of the right and left eyes showing cecocentral scotomas of the right eye worse than the left.

What is your diagnosis?

Decreased vision

The diagnosis of optic neuropathy can be complex. Therefore, it is important to get a comprehensive history to rule out all potential causes. The differential diagnosis includes mitochondrial optic neuropathy, traumatic optic neuropathy, compressive optic neuropathy, optic neuritis, infiltrative optic neuropathy and ischemic optic neuropathy.

Our patient had no history of trauma, ruling out a traumatic optic neuropathy. Her age, lack of risk factors and bilateral cecocentral scotomas ruled out ischemic optic neuropathy. Optic neuritis, infiltrative optic neuropathy and compressive optic neuropathy were unlikely given a normal MRI of the brain and spine. Consequently, the focus was placed on mitochondrial optic neuropathy. Genetic testing returned positive for LHON 11778 G to A mutation consistent with Leber’s hereditary optic neuropathy.

Discussion

Mitochondrial optic neuropathies can be broken up into hereditary and acquired causes. Hereditary causes include Leber’s hereditary optic neuropathy (LHON), autosomal dominant optic atrophy, Behr’s syndrome and familial dysautonomia. Acquired causes include toxic optic neuropathy (eg, methanol), drug-induced optic neuropathy (eg, ethambutol) and nutritional deficiency (associated with tobacco and alcohol abuse). A thorough history is critical to help narrow the list of differential diagnoses, and prompt diagnosis is important to prevent further damage from any nutritional deficiencies or toxic causes.

LHON is a mitochondrial inherited disease occurring most frequently in males between the ages of 10 and 30 years old. LHON is characterized by significant, abrupt, sequential, painless vision loss. Typically, initial vision loss is monocular followed by abrupt visual loss in the fellow eye. It can be quite devastating. Most frequently, visual acuities are measured worse than 20/200. Cecocentral visual field defects and decreased contrast sensitivity and color vision (most commonly on the red-green axis) are other common characteristics.

LHON has a characteristic triad to help hasten the diagnosis. However, many never exhibit these characteristic signs even at the time of profound vision loss, often making this a challenging diagnosis. This triad includes circumpapillary telangiectatic microangiopathy, pseudoedema of the nerve fiber layer around the disc, and absence of papillary leakage on fluorescein angiography. Imaging often shows ganglion cell complex thinning as well as papillomacular retinal nerve fiber layer (RNFL) thickening lasting for weeks, later followed by temporal RNFL thinning. In several cases, generalized RNFL thinning is also seen. Electrophysiology (PVEP and PERG) is also abnormal.

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Given the devastating visual loss, a great deal of research has been conducted, looking into potential treatments and cures for LHON. Idebenone, a member of the quinone family, has shown some promise based on several small case studies. Recently, a larger 24-week multicenter masked randomized placebo-controlled trial was performed. The study included 85 LHON patients with 11778, 3460 and 14484 mutations who were given idebenone 900 mg/day. Results showed no statistical significance in visual acuity recovery, although the authors noted possible improvement in color contrast sensitivity and increase of RNFL thickness. Most importantly, the study showed idebenone was well tolerated without significant side effects.

Other studies have evaluated the protective effect of estrogen. One study showed in vitro cell lines with LHON mutations develop less apoptosis in the presence of estrogen. Other potential neuroprotective free radical scavengers including coenzyme Q (CoQ) analogues and EPI-743 are in early stages of investigation.

Finally, some of the most promising treatments lie with gene therapy. While still early in the process, animal studies with rats have demonstrated safe allotopic delivery of the normal human ND4 subunit gene into the vitreous cavity of the LHON animal model eye, which the authors found may prevent retinal ganglion cell loss. These results give some hope that human therapy for LHON is not far behind.

Further research is focusing on which patients would benefit most from gene therapy. Lam and colleagues found that OCT RNFL thickness averages 72 µm for up to 32 months after visual loss, but drops to an average of 47 µm in patients presenting after 32 months. This could suggest up to a 3-year window after initial visual loss in which to restore some visual function.