Leber’s optic neuropathy associated with disseminated white matter disease: A case report and review

1. Introduction 

Leber’s hereditary optic neuropathy (LHON), the most common mitochondrial disease with a prevalence of 1/25,000, is clinically characterized by a bilateral subacute loss of central vision following optic nerve involvement which generally develops into blindness in a few months [1]. In most cases, both eyes are affected sequentially with a median inter-eye delay of eight weeks [2]. LHON is usually maternally inherited but sporadic cases may occur. Three mtDNA mutations (the most frequent G11778A, G3460A and T14484C) account for at least 90% of LHON families. More than 30 mutations have been described to date [1], [2].

Additional neurological features have rarely been reported including parkinsonism, dystonia, seizures, myoclonus, demyelinating polyneuropathy, cerebellar ataxia and Leigh-like encephalopathy. Moreover, a multiple sclerosis-like phenotype (MSL) has also been described, mainly in female patients, with variable neurological features, ovoid white matter lesions on brain MRI and oligoclonal bands in the CSF [3]. We present here one additional sporadic male patient displaying LHON-MSL associated with the prevalent G11778A mutation.

2. Case report 

The patient, a 31-year-old man, manifested a subacute bilateral decrease of central vision. He mentioned only past medical history of the occurrence one month before transitory bilateral legs paresthesias, which spontaneously recovered in two weeks. Family history revealed only essential postural tremor in his father’s. Ophtalmological examination showed a total central vision loss of the right eye and visual left acuity was measured at 1/10. Fundoscopy revealed right optic atrophy but left side was normal (Fig. 1). Fluorescein angiography confirmed right optic atrophy without swelling or haemorrhages. Visual evoked potentials were bilaterally inflected with decrease of velocities and amplitudes. CSF examination revealed 37cells/mm3 and oligoclonal bands not present in the serum, while IgG index was increased (1.6, normal <0.65). Extensive searches for infections were negative in CSF and in blood. Brain MRI showed four sustentorial ovoid white matter hyperintense lesions and one in the posterior fossa on T2 weighted images (Fig. 2) with no enhancement after gadolinium injection. Spinal cord MRI showed a slight hyperintensity at T4 level on T2 images. As an inflammatory optic neuritis was suspected, the patient received intravenous methylprednisolone (1g/day) for three days without improving his vision. Two months later, a novel episode of central vision loss occurred with bilateral impaired colour and contrast perception. He also complained of symmetric legs burning pains and thighs’ paresthesias. Sensitive abnormalities with decreased vibration and thermoalgic perception on the right leg and on the right hand and pyramidal signs on the four limbs with diffuse increased deep tendon reflexes predominating on the left side, left Babinski sign, bilateral Hoffman signs and non-persistent ankle clonus were present on neurological examination. Cerebral and spinal cord MRI images were unchanged. Antinuclear antibodies, rheumatoid factors, anticardiolipid antibodies were negative. B9 and B12 vitamins levels were in the normal ranges. Lactates and pyruvates were normal before and after physical effort. In CSF, 12cells/mm3 were detected, proteins isoelectrofocalisation showed three oligoclonal bands and lactates were normal. The diagnosis of severe bilateral optic neuritis not improved by steroids was still considered. Seven courses of plasmapheresis were undergone according to the procedure used in neuromyelitis optica or severe demyelinating attacks. The patient felt subjective improvement of perception for light and contrast in the left eye after the fifth course. He then received six courses of intravenous cyclophosphamide at a dosage of 1200mg per month. LHON was diagnosed during the third course by identifying a homoplasmic G11778A mutation in the mtDNA. This G11778A mutation was also present and homoplasmic in the healthy mother of the patient. She had normal optic fundus at age 62 years. Mild improvement of visual acuity and leg pain reduction were noticed. This treatment was followed by four courses of intravenous mitoxantrone (19.2mg each month) but it was stopped because of persistent neutropenia. A treatment by ibedenone was initiated at a dosage of 10mg/kgday then increased to 15mg/kgday. However, the patient’s visual acuity was irreversibly impaired and he definitely became blind six months after the beginning of this treatment. No other clinical episodes and unchanged MRI anomalies were noted during this period of three years’ follow-up. His latest neurological examination was fully normal regardless of his blindness.

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Fig. 1. Initial fundoscopy shows optic atrophy on the right eye, but no abnormalities on the left eye at this stage.

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Fig. 2. First brain MRI: T2 FLAIR weighted images show (A) cerebellar peduncular hyperintensity (arrow), (B) two periventricular hyperintensities (arrows).

3. Discussion 

This patient had severe bilateral optic nerve impairment associated with multifocal white matter lesions in the brain and oligoclonal bands in CSF. Presence of several brain MRI lesions did not suggest the diagnosis of Devic’s neuromyelitis optica. Immunosuppressive treatment was first initiated considering a potential multiple sclerosis (MS) revealed by severe optic neuritis. Initial visual acuity improvement obtained with plasmapheresis and cyclophosphamide argued for an inflammatory contribution, at least partial, in the development of this visual deficiency. However, the atrophic process led to irremediable blindness in 18 months. The severity of vision impairment led us to evocate the diagnosis of LHON-MSL which was molecularly confirmed. Treatment using mitoxantrone was then introduced, replaced by idebenone after occurrence of adverse effects, as these drugs may provide gain in LHON-MSL [4], [5], but the patient displayed no improvement of his vision. At the end of the three years’ follow-up, he has not complained from additional neurological troubles.

A bilateral vision impairment leading to blindness is present in 86% of the 17 LHON-MSL patients reported in the literature (Table 1). The sex ratio was 1.8:1 (11 females and 6 males). Onset generally occurs during the second or third decade (mean onset age: 31 years±7). Clinical CNS manifestations appear highly variable, as in MS, including medullar, cerebellar and sustentorial features. These features may precede optic impairment for 10 years, although they follow it in 70% of the cases until 19 years later. The average onset of CNS features was 4.3 years after the visual decline onset. Their evolution can assume a relapsing course (9/11) but, in some cases, a progressive worsening was observed initially or soon after onset of neurological symptoms (5/10). At the end of clinical follow-up (mean duration: 13 years from the start of the disease, 9 years from the first neurological non-visual feature), 12 of 14 patients were disabled regardless of the visual handicap. Among these latter patients, 75% had walking troubles that led half of them to wheelchair.

Table 1. Main clinical, imaging and biological data of the 17 patients with LHON-MSL reported to date

	Characteristics	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17
	Gender	F	F	F	F	F	F	M	F	M	M	M	F	F	M	F	F	M
	Age at onset (years)	26	25	28	34	33	32	31	50	29	24	17	26	25	34	36	40	31
	Signs at onset	UON	UON	UON	NF	UON	UON	NF	UON	UON	UON	UON	BON	BON	UON	NF	NF	NF
	WMH on MRI at onset	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	−	−	+	−	+
	OCB in CSF at onset	−	ND	+	ND	ND	ND	ND	ND	+	ND	ND	ND	−	−	+	−	+
	Interval between ON and NF	6 Mth	18 Yrs	1 Yrs	9 Yrs	11 Yrs	16 Yrs	10 Yrs	3 Yrs	None	7 Yrs	18 Mth	19 Yrs	13 Yrs	9 Yrs	6 Mth	10 Yrs	1 Mth
	Progression of the disease	R/P	ND	R/P	R	R	R	R	P	P	R	ND	ND	ND	ND	R/P	R	−
	WMH on MRI during evolution	+	+	+	ND	+	+	+	+	ND	+	+	+	+	+	+	+	+
	OCB in CSF during evolution	−	+	−	ND	ND	−	+	+	ND	ND	+	+	ND	ND	ND	+	+
	Follow-up duration (years)	14	21	11	28	23	ND	13	11	11	8	4	24	17	10	4	12	3
	Blindness at end of follow-up	+	+	+	+	+	+	+	+	+	+	−	ND	ND	ND	+	−	+
	Severity of motor handicap at end of follow-up	Mi	Mo	Se	Mo	Mi	Mo	Mo	Se	Se	Mi	ND	ND	Se†	Mo	Mo	−	−
	Treatments used*:		ND	ND	ND	ND		ND	ND				ND
	IM ACTH	+					−			−	−	−		−	−	−	−	−
	PO B vitamins	−					+			+	−	−		+	+	−	−	−
	IV methylprednisolone	−					−			+	+	−		+	−	+	+	+
	IV cyclophosphamide	−					−			−	−	+		−	−	−	−	+
	IV immunoglobulins	−					−			−	−	+		−	−	−	−	−
	IV mitoxantrone	−					−			−	−	+‡		−	−	−	−	+
	PO idebenone	−					−				+‡	−		−	−	+	+	+
	Efficiency of treatment on vision	−	/	/	/	/	ND	/	/	−	−	+	/	−	−	−	−	−
	Efficiency of treatment on NF	−	/	/	/	/	ND	/	/	−	+	−	/	−	−	−	−	+
	Mutation G11778A	+	+	+	+	+	+	+	+	+	+	+	+	−	+	+	−	+
	% of mutated mtDNA	>95	>95	>95	>95	>95	>95	100	100	100	100	100	ND	ND	100	100	100	100
	References	[3]	[3]	[3]	[3]	[3]	[3]	[13]	[7]	[7]	[5]	[4]	[14]	[9]	[15]	[16]	[16]	Our case

* The treatment which improved the features are marked with ‡ for each patient. M: male; F: female; BON: simultaneous bilateral optic neuritis; UON: unilateral optic neuritis; NF: neurological features; R: relapsing course; P: progressive course; R/P: relapsing course secondary progressive; WMH: white matter hyperintensities; OCB: oligoclonal bands; PO: per os; IM: intramuscular; IV: intravenous; Yrs: years; Mths: months; +: present; −: absent; Mi: mild (neurological handicap without impaired mobility); Mo: moderate (impaired mobility); Se: severe (wheelchair); ND: no data; †: deceased.

Heteroplasmy contributes to the incomplete penetrance observed in LHON with a reduced risk of visual failure in patients with <60% mutated mtDNA in their blood [6]. Otherwise, all the previous LHON-MSL patients had a very high rate of mutated mtDNA (>95%) compatible with homoplasmic mutations (Table 1). These data would suggest that homoplasmy may be a risk factor for the occurrence of associated neurological features and of a more severe phenotype in LHON as observed in LHON-MSL, although the size of the population studied is small.

The respective roles of inflammation and energetic metabolism dysfunction in the development of cerebral white matter lesions remain to be elucidated in LHON-MSL. LHON-MSL mutations affect mtDNA coding for mitochondrial respiratory chain complex I’s subunits (11778/ND4, 3460/ND1, 14484/ND6). These mutations lead to altered mitochondrial metabolism, chronic increase of oxidative stress and finally to retinal ganglion cells and optic nerve axons degeneration [7]. Imaging evidences for decreased brain energy reserves have been reported in LHON even in the absence of MS-like signs [8]. Treatment with idebenone, an analogue of coenzyme Q10 which stimulates ATP formation, could improve visual recovery [9]. It showed efficiency on neurological features in one case. Alternatively, the frequent presence (87%) of oligoclonal bands in MS-LHON (Table 1) argues for an inflammatory auto-immune component in the pathological process. This is also supported by the positive effects on visual recovery previously reported after mitoxantrone use [4] and after plasmapheresis and cyclophosphamide therapy in our patient, even transient and mild. Moreover, MRI and MR spectroscopy showed lesions compatible with a chronic MS [3], [8]. A recent neuropathological study of one LHON-MSL female patient revealed concomitant classical and atypical MS lesions [10]. Finally, increased production of reactive oxygen species plays a relevant role in retinal ganglion cells’ death in LHON [11] and free radicals can lead to the formation of new antibodies involved in the inflammatory process of experimental acute encephalomyelitis [12].

Thus, the genetically determined neurodegenerative process of LHON might lead to the formation of new epitopes on CNS membranes triggering early immunological events in addition to the primary degeneration. In this context, immunosuppressive treatments may have succeeded in stopping this immunological process but not in stopping degeneration of the optic nerves. Considering all these data, we propose to treat these patients early with both antioxidative and immunosuppressive drugs in order to prevent the risk of severe disabling motor handicap (Table 1).