Differentiating Leber’s Hereditary Optic Neuropathy from Optic Neuritis in a Clinical Setting

Dear Editor,

Leber’s hereditary optic neuropathy (LHON) is a rare, maternally inherited disorder that predominantly affects young men between 15 and 35 years of age.[1] Clinically, LHON initially presents with features that mimic optic neuritis (ON), including acute or subacute progressive vision loss in one or both eyes (BE). Unlike ON, vision loss in LHON tends to be painless, predominantly central, and progresses through four stages, namely: (I) asymptomatic; (ii) subacute (within 6 months from onset); (iii) dynamic (6–12 months from onset); and (iv) chronic (>12 months), with each stage showing distinct optical coherence tomography (OCT) changes. Further, cigarette smoking and alcohol consumption are known to trigger and aggravate symptoms. Lack of treatment response further supports the diagnosis.[2] Here, we discuss two cases of LHON, which illustrate the heterogeneous presentation of the disease, highlight the clinical and diagnostic similarities with ON, and explain how they were differentiated.

Patient A was a 32-year-old male who developed sequential visual loss, beginning with acute visual loss in the right eye (RE), which worsened to counting fingers (CF) at 1 m within 2 days. He was evaluated and treated for acute ON, receiving intravenous (IV) methylprednisolone followed by oral prednisolone, but noted no improvement. Review of his reports showed that fundus examination and perimetry, performed 1 month after onset, revealed bilateral disc edema and bilateral cecocentral scotoma, respectively, including in the asymptomatic left eye (LE) [Supplementary Table 1]. Five months later, he developed acute-onset painless vision loss in the LE, which again became severe within 2–3 days. He presented to our center 8 months later, at which time he had chronic visual loss of 16 months in the RE and dynamic visual loss of 11 months in the LE. His ophthalmic examination and MRI findings at these stages are described in Supplementary Table 1 [Figures 1b, 2a and 2b].

Supplementary Table 1.

Clinical features and ophthalmic examination at different stages in two patients

Ophthalmic and MRI evaluation at available stages for each eye			VA	Fundus	VEP	Perimetry	OCT	MRI brain
Patient A	Right eye	Subacute	CF at 1 meter	Hyperaemia with blurred disc margin	Non recordable	Cecocentral scotoma	NA	Normal
		Chronic	PL	Pale disc	Non recordable	NA	Diffuse RNFL thinning	T2/ STIR hyperintensity involving intraorbital, intracanalicular, intracranial optic nerve and optic chiasm
	Left eye	Presymptomatic	20/20	Hyperaemia with blurred disc margin	Normal	Cecocentral scotoma	NA	Normal
		Dynamic	HM at 1 meter	Pale disc	Non recordable	NA	Diffuse RNFL thinning	T2/ STIR hyperintensity involving intraorbital, intracanalicular, intracranial optic nerve and optic chiasm without contrast enhancement
Patient B	Right eye	Subacute	6/60	Disc hyperaemia with early pallor	Non recordable	Normal at 3 weeks, Enlarged Central scotoma at 3 months	TQ Normal, SQ and NQ thickening	No optic nerve signal changes.
	Left eye	Subacute	CF 1 meter	Disc hyperaemia with early pallor	Non recordable	Normal at 3 weeks, Enlarged Central scotoma at 3 months	TQ thinning, SQ and NQ thickening	No optic nerve signal changes.

CF: Counting Finger, HM: Hand Movements, MRI: Magnetic Resonance Imaging, NA: Not available, NQ: Nasal Quadrant, OCT: Optical Coherence Tomography, PL: Perception of Light, RNFL: Retinal Nerve Fiber Layer, SQ: Superior Quadrant, STIR: Short Tau Inversion Recovery, TQ: Temporal Quadrant, VA: Visual acuity, VEP: Visual Evoked Potential

Figure 1.

(a) OCT in patient B at 3 months of onset showing temporal RNFL thinning and superior and inferior RNFL thickening in the left eye. (b) OCT in patient A in the chronic stage showing global RNFL thinning. INF: inferior, NAS: nasal, NI: nasal inferior, NS: nasal superior, N/T: nasal/temporal, OCT: optical coherence tomography, OD: oculus dexter/right eye OS: oculus sinister/ left eye, PMB: papillo-macular bundle, RNFL: retinal nerve fiber layer, SUP: superior, TI: temporal inferior, TMP: temporal, TS: temporal superior

Figure 2.

(a) Axial T2W and (b) coronal MRI images in patient A showing bilateral optic nerve and optic chiasm hyperintensity with bilateral optic nerve thinning (arrowheads). MRI: Magnetic resonance imaging, T2W: T2 Weighted

Patient B, a 40-year-old male, developed bilateral sequential painless vision blurring—left followed by right—within a week, which progressed by the third week to visual acuity (VA) of 6/60 in the RE and CF at 3 m in the LE, along with bilateral dyschromatopsia, disc hyperaemia, and normal perimetry [Supplementary Table 1]. He received 5 g of IV methylprednisolone over 5 days, followed by oral prednisolone without improvement. At his first evaluation with us, 3 months from onset (subacute stage), VA was 6/60 in the RE and CF at 3 m in the LE, same as before treatment. His family history revealed bilateral vision loss in his elder brother at the age of 18 years, without recovery. His ophthalmic and Magnetic resonance imaging (MRI) findings at this subacute stage are described in Supplementary Table 1 [Figures 3a, 3b, and 1a].

Figure 3.

(a) Fundus examination in patient B in the subacute stage shows hyperaemia with patchy area of disc pallor in both eyes. (b) Visual field examination in patient B in the subacute stage shows cecocentral scotoma in both eyes

Both patients underwent mitochondrial genome sequencing and were found to have the homoplasmic mt11778G>A mutation in the mitochondrial ND4 gene, pathognomic of LHON.

Both patients presented at different clinical stages. Chronologically, patient A had chronic and dynamic stages in different eyes, whereas patient B presented in the subacute stage. Vision loss in LHON is characteristically painless and sequential (within weeks to months) or bilateral and simultaneous (25%), with VA deteriorating rapidly to 20/200 or worse, as seen in both our cases.[3] Periocular and retrobulbar pain, headache, positive phenomenon such as phosphenes and scintillation, Pulfrich phenomenon, and Uhthoff phenomenon are conspicuously absent and should be queried to exclude the alternative diagnosis of ON [Supplementary Table 2].

Supplementary Table 2.

Clinical and ophthalmic examination features differentiating LHON from ON

	LHON	ON
Characteristic of vision loss	Subacute monocular or binocular painless	Subacute monocular, binocular vision loss associated with ocular pain and aggravated on eye movements
Evolution of symptoms	Progressive	Monophasic, Recurrent, Self-resolving, immune suppression dependant, Rarely progressive
Stages	(I) Asymptomatic; (II) Subacute (within 6 months from onset); (III) Dynamic (6–12 months from onset); (IV) Chronic (>12 months)	(I) Acute phase <7 days (II) Subacute phase 1 week – 3 months (III) Chronic phase >3 months
Accompanying clinical features		Photophobia, Periocular and/or retrobulbar pain, Positive phenomenon like phosphenes and scintillation, Pulfrich phenomenon, Uhthoff phenomenon
Nadir	At 6 months	At 1 month
Prodromal symptoms	Absent	May precede onset of vision loss
RAPD	Absent	Present
Dyschromatopsia	Present	Present
VA	Usually <20/200	Varying from 20/20 to No PL
Fundus	Disc hyperaemia, peripapillary telangiectasia and vessel tortuosity, Normal	Papillitis, peripapillary haemorrhage, peripapillary wrinkles, Optic nerve head swelling, Normal
FFA	Telangiectatic changes of peri-papillary arteries with frequent arterio-venous shunting, no fluorescein dye leakage	Fluorescein dye leakage present
VF	Central and cecocentral scotoma, Diffuse in chronic stage	Diffuse, Central, Cecocentral, Altitudinal defects, arcuate defects, Vertical step defects
OCT	Presymptomatic stage- Temporal RNFL thickening Onset-Temporal thickening GCL thinning 3 months- Temporal thinning Superior, Inferior, Nasal quadrant thickening 9 months- Diffuse RNFL thinning	Presymptomatic stage- NA Onset- Normal or diffuse RNFL thickening GCL thinning onset at 5 weeks 3 months- RNFL thinning starts, Temporal predilection in MS, Diffuse in NMOSD 9 months- Diffuse RNFL thinning
MRI brain/ MRI orbits	T2 hyperintense lesion in optic nerve, optic chiasm, rarely optic radiation. Infrequent contrast enhancement in subacute stage	T2 hyperintense long or short segment lesion in optic nerve, optic chiasm, optic radiation. Contrast enhancement in active lesions. Optic nerve sheath enhancement, periorbital fat signal changes

FFA: Fundus Fluorescein Angiography, GCL: Ganglion Cell Layer, LHON: Leber’s Hereditary Optic Neuropathy, MRI: Magnetic Resonance Imaging, NA: Not applicable, NMOSD: Neuromyelitis Optica Spectrum Disorder, OCT: Optical Coherence Tomography, ON: Optic Neuritis, PL: Perception of Light, RAPD: Relative Afferent Pupillary Defect, RNFL: Retinal Nerve Fiber Layer, VA: Visual Acuity, VF: Visual Field

The vision loss was static in patient A at presentation, while it was still evolving in patient B. The nadir of vision loss in LHON is typically reached around 6 months. Attention to pupillary reflexes at this stage is important. Relative afferent pupillary defect (RAPD) is usually not seen in LHON and was absent in both patients. A significant observation in our report is that patient A showed disc hyperemia and perimetry defects in BE, although only the RE was clinically involved. This patient developed clinical symptoms of vision loss in LE five months after the initial fundus and perimetry changes observed. These presymptomatic findings are frequently encountered in LHON. The early clinical stage shows disc hyperemia, vessel tortuosity, and peripapillary telangiectasia, whereas the chronic stage shows disc pallor.[4] Fundus fluorescein angiography in the acute stage shows peripapillary telangiectasia, often with arterio-venous shunting, and absence of fluorescein dye leakage, which helps differentiate it from ON. Perimetry shows enlarging central or cecocentral scotoma with clinical progression, suggesting selective involvement of the papillomacular bundle in the early stages.[5] Figure 3b showed a cecocentral scotoma in the subacute stage in patient B.

OCT findings are highly significant and help differentiate LHON from ON. At the onset of visual symptoms, OCT shows temporal thickening, which gradually starts thinning by 3 months, while the superior and inferior quadrants begin to show thickening, followed by the nasal quadrant. As the optic atrophy starts after 3 months, the superior, nasal, and inferior quadrants gradually start thinning, with global thinning noted at 6–9 months.[6] In patient B [Figure 1a], at 3 months after disease onset, the temporal retinal nerve fiber layer (RNFL) was thinned, the superior and inferior RNFL were thickened, while the nasal RNFL remained normal. This unique topographic changes in LHON patients results from the differential involvement of nerve fibres at different stages. MRI findings in LHON have been well documented. Hyperintensity of the optic nerves and chiasm has been noted and was observed in the study patient A [Figures 2a and 2b]. A minority of cases show gadolinium enhancement. There are also reported cases of LHON patients with asymptomatic white matter lesions that resemble MS.[7]

Both of our patients had a severe form of the mutation (mt11778G>A), which holds a poor prognosis with severe RNFL atrophy when compared to all other mutations.[8] Both our patients were treated with mitochondrial cocktail treatment[9] and did not show a significant response to it. In addition, patient B was given idebenone, which has been shown to reduce the progression of the disease when started early. He did not report a significant improvement in clinical progression at 8 weeks’ follow-up.

To conclude, acute or subacute sequential painless vision loss, particularly in a young male; absence of RAPD; a positive family history; and characteristic perimetry and OCT findings, along with persistent optic disc swelling despite steroid treatment and poor response to steroids in general, are the features that help early differentiation of LHON from ON in a clinical setting.

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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.