Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder, characterized by sequential occurrence of acute or subacute bilateral visual loss and centrocecal scotomas. In most patients, there are no other neurologic manifestations, and neuroimaging of the brain is normal. However, additional neurologic features rarely have been described including the occurrence of LHON and multiple sclerosis (MS) (1–3). We describe a patient with symptoms compatible with LHON, confirmed by genetic testing, who also had reversible bilateral occipital lesions associated with headache and epileptic seizures.
A 13-year-old boy developed blurred vision in his both eyes. He was the firstborn child of a healthy nonconsanguineous Chinese couple, and the family history was unremarkable. The patient initially was diagnosed with bilateral optic neuritis and underwent intravenous pulse methylprednisolone therapy without improvement in vision.
Forty-seven days after the onset of symptoms, the patient complained of headache followed by 4 generalized tonic-clonic seizures. His blood pressure was normal, and there was no history of a seizure disorder. He was diagnosed with viral encephalitis and treated with acyclovir (50 mg every 8 hours for 2 weeks) and phenytoin (200 mg 3 times a day). Subsequently, he had no further seizures.
On day 75 after the onset of symptoms, he was referred to our Neurology Department for further evaluation. Visual acuity was 20/400 bilaterally, visual fields showed central scotomas in each eye, and both optic discs were pale. Neurologic examination was otherwise normal.
No evidence of abnormality was not found in complete blood count, urinalysis, biochemistries, including erythrocyte sedimentation rate and C reaction protein. Markers of autoimmune diseases were negative and included antinuclear antibody, antineutrophil cytoplasmic antibody, anticardiolipin antibodies and rheumatoid factor. Examination of the cerebrospinal fluid (CSF) on 2 occasions was unremarkable. Serum and CSF viral antibody tests were negative for herpes simplex virus (HSV-1 and HSV-2), varicella zoster virus, Epstein-Barr virus, and measles virus. Viral polymerase chain reaction was not done on the CSF. Electroencephalography was normal.
Magnetic resonance imaging (MRI) of the brain performed 42 days after the symptom onset, and prior to seizures, was normal. Five days following the onset of seizures, MRI revealed high signal intensity lesions involving the occipital lobes on both T2 and fluid-attenuated invasion recovery (FLAIR) images (Fig. 1A). Diffusion-weighted imaging showed no evidence of restricted diffusion. Sixteen days after the onset of seizures, there was partial resolution of the signal change in both occipital lobes (Fig. 1B), and by 34 days, MRI was normal in appearance (Fig. 1C).
In evaluating our patient, we were suspicious of a mitochondrial disorder including LHON and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Muscle biopsy (left brachial biceps) was performed, and no ragged red fibers were found. Screening mitochondrial DNA (mtDNA) for 3 primary LHON point mutations revealed a homoplasmic mtDNA G11778A mutation in lymphocytes. MELAS mtDNA point mutations (A3243G and A3271T) were absent. Large-scale rearrangements of mtDNA extracted from muscle were screened for Southern blotting of DNA and were not found. Sequencing the entire mtDNA coding region excluded rare mutations associated with MELAS, myoclonic epilepsy with ragged red fibers, or LHON/MELAS syndrome. No other pathogenic mutations were found in all mtDNA transfer RNA, complex I, complex III, and complex V genes except for G11778A mutation. The diagnosis of LHON was established, and the patient was treated with coenzyme Q10.
The presence of the G11778A mutation was confirmed in our patient’s younger brother, who is clinically unaffected. The mother of the proband is asymptomatic and refused evaluation.
While the clinical presentation and results of genetic testing secured the diagnosis of LHON in our patient, the occurrence of seizures with LHON is rare (1,4). Serial brain MRI in our case revealed complete resolution of abnormal T2 and FLAIR signal changes in the occipital lobes, consistent with posterior reversible encephalopathy syndrome (PRES).
PRES is characterized by seizures, altered mental state, headache, focal neurologic deficits, and visual disturbances (5–7). Cerebral edema most often is detected in the parieto-occipital region but may occur in the temporal lobe, temporal-occipital junction, cerebellum, and, rarely, in the basal ganglia and brainstem. It commonly occurs at the border zones of cerebral arterial territories. Hypertension is the most frequent predisposing cause of PRES, but the syndrome has been reported in a wide variety of settings, including solid organ transplantation and medications used to prevent rejection, renal disease, autoimmune disorders, severe infection, and mitochondrial disorders (8,9). The etiology of PRES in our patient is unclear.
Headache and seizures also may occur in stroke-like episodes of MELAS. In addition, LHON/MELAS overlap phenotype associated with a complex I or complex V subunit gene mutation had been reported (10,11). However, our patient did not have ragged red fibers on muscle biopsy, and the sequence analysis of entire mtDNA coding region revealed no other pathogenic mutations in all mtDNA transfer RNA, complex I, complex III, complex IV, and complex V genes.
The most common mutations of LHON are missense mutation in mitochondrial encoded complex I subunits, which are 11778 G>A, 3460 G>A, and 14484 T>C. All of these mtDNA mutations have been reported to be associated with white matter disorders typically in a periventricular distribution resembling MS (4,12–15). Several pathogenic mechanisms have been proposed: 1) impairment of cellular energy generation with ATP depletion; 2) this energy crisis causes lipid peroxidation and oxidative damage of protein, causing damage to the mitochondrial membrane; 3) altered mitochondrial permeability leads to initiation of apoptotic cell death; and 4) vascular changes with the accumulation of abnormal mitochondria in both endothelial and smooth muscle cells of the blood vessel walls (15,16). Magnetic resonance spectroscopy studies of LHON with the G11778A mutation have demonstrated abnormal mitochondrial energy metabolism in the occipital lobe (17). Grazina et al (12) reported that in individuals harboring the 11778G>A mutation, possible association with other neurologic disturbances may be explained by heteroplasmy, different tissue distribution of mutant mtDNA, and other genomic and environmental modifiers. It may be that a variety of these factors contributed to the unusual clinical course of our patient.
The authors are grateful to the family members of the patients mentioned in this report for their collaboration. They thank Dr. Rabi Tawil (University of Rochester Medical Center) for critical reading of the manuscript and helpful suggestions. They are also grateful for the financial support from the Beijing Municipal Health Bureau on the “215” high-level health and technical personnel training project.
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