Clinical spectrum of Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778, and 14484 in genes encoding subunits of Complex 1 of the respiratory chain. Molecular diagnosis has expanded the spectrum of the LHON phenotype and prompted investigation into optic neuropathies due to demyelinating disease, glaucoma, tobacco/alcohol amblyopia, and nutritional optic neuropathy. While mitochondrial mutations are required for LHON disease expression, other genetic or epigentic factors must play a role in disease penetrance and expression. Proposed determinants of disease include heteroplasmy, an X-linked vision loss susceptibility locus, environmental factors, and secondary mitochondrial mutations.     

A hereditary chiasmal optic neuropathy

The purpose of this study was to examine hand sensibility of surgeons wearing single and double latex gloves. Evaluation of hand sensibility, including cutaneous pressure thresholds, moving two-point discrimination, and static two-point discrimination, was performed on 25 surgeons (mean age 45 years). The dominant hand index finger was assessed with no glove, single glove, and double glove. The majority of surgeons had a moving and static two-point discrimination of 2 or 3 mm. The lowest cutaneous pressure thresholds were found when measured with no gloves and increased with single and double gloves. Statistically significant differences in cutaneous pressure thresholds using Semmes-Weinstein monofilaments were found for gloves versus no gloves (p < 0.0003) and single versus double gloves (p = 0.0003). Statistically significant differences in moving two-point discrimination were found for no gloves versus double gloves (p = 0.05) and single versus double gloves (p = 0.02). In conclusion, we found significant differences in hand sensation when measured with single and double gloves.     

Juvenile pilocytic astrocytoma masquerading as amblyopia

PURPOSE: A healthy 13-year-old girl, previously diagnosed with amblyopia in her right eye, was seen in consultation after her vision continued to decrease. METHODS: A complete ophthalmologic examination including visual field testing and optic nerve photography was performed in the neuro-ophthalmologic clinic. Magnetic resonance imaging study was also obtained. RESULTS: Visual sensory deficits and pale optic nerves were noted on clinical examination. Visual field testing showed a chiasmatic junctional defect. Magnetic resonance imaging verified a large chiasmatic mass, histologically proven to be a juvenile pilocytic astrocytoma. CONCLUSION: Early recognition of signs and symptoms of chiasmatic lesions is essential for preventing visual loss.     

Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy

Mitochondrial DNA from two genetically unrelated patients carrying the mutation at position 11778 that causes Leber's hereditary optic neuropathy has been transferred with mitochondria into human mtDNA-less rho0206 cells. As analyzed in several transmitochondrial cell lines thus obtained, the mutation, which is in the gene encoding subunit ND4 of the respiratory chain NADH dehydrogenase (ND), did not affect the synthesis, size, or stability of ND4, nor its incorporation into the enzyme complex. However, NADH dehydrogenase-dependent respiration, as measured in digitonin-permeabilized cells, was specifically decreased by approximately 40% in cells carrying the mutation. This decrease, which was significant at the 99.99% confidence level, was correlated with a significantly reduced ability of the mutant cells to grow in a medium containing galactose instead of glucose, indicating a clear impairment in their oxidative phosphorylation capacity. On the contrary, no decrease in rotenone-sensitive NADH dehydrogenase activity, using a water-soluble ubiquinone analogue as electron acceptor, was detected in disrupted mitochondrial membranes. This is the first cellular model exhibiting in a foreign nuclear background mitochondrial DNA-linked biochemical defects underlying the optic neuropathy phenotype.     

On the many faces of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.     

Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype

To clarify the bioenergetic relevance of mtDNA mutations in Leber's hereditary optic neuropathy (LHON), we investigated affected individuals and healthy carriers from six Italian LHON families harboring the 11778/ND4 and the 3460/ND1 mtDNA mutations. The enzymatic activities of mitochondrial complex I and its sensitivity to the potent inhibitors rotenone and rolliniastatin-2 were studied in mitochondrial particles from platelets, in correlation with mtDNA analysis of platelets and leukocytes. In platelets homoplasmic for mutant mtDNA, both 11778/ND4 and 3460/ND1 mutations induced resistance to rotenone and the 3460/ND1 mutation also provoked a marked decrease in the specific activity of complex I. Individuals heteroplasmic in platelets for either mutation showed normal biochemical features, indicating functional complementation of wild-type mtDNA. There was no correlation between the clinical status and mtDNA homo/heteroplasmy in platelets, but the biochemical features correlated with the mitochondrial genotype of platelets. In some cases, the degree of mtDNA heteroplasmy differed in platelets and leukocytes from the same individual with a prevalence of wild-type mtDNA in the platelets. These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues. The differential tissue heteroplasmy may be more relevant than previously thought in determining disease penetrance.     

Leber''s hereditary optic neuropathy: a genetic disorder of the eye

Susceptibility to bleeding in the patient treated with coumarin derivatives poses difficult management issues for the dentist. Classic monitoring for anticoagulation relied on the prothrombin time, but reagent variability issues have caused the emergence of the International Normalized Ratio (INR) as an alternative, and possibly more reliable, laboratory test for the assessment of a patient's anticoagulation status. The literature suggests that an INR range of 1.5 to 2.5 represents the most appropriate level of anticoagulation for the surgical patient. That is, at this INR, some protection is afforded against thrombo-embolic events without significantly sacrificing effective post-operative hemostasis. Since the patient with an INR value within the recommended range is still anticoagulated, he/she is still at risk for post-operative bleeding. Adherence to local hemostatic measures--such as pressure, topical thrombin, alveolar-placed resorbable sponges, and primary wound closure--offers the patient important adjunctive protection against post-operative bleeding.     

Leber hereditary optic neuropathy. Electron microscopy and molecular genetic analysis of a case

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disorder characterized by bilateral central visual loss typically in early adulthood. Few histopathologic studies, including ultrastructural and molecular genetic analysis, have been reported. METHODS: Ocular tissue was obtained postmortem from an 81-year-old woman with LHON from the Queensland 1 pedigree characterized by mutations at nucleotide positions 4160 and 14484. Routine histopathologic studies, electron microscopy, electron-probe analysis, and molecular genetic analysis were performed. RESULTS: Marked atrophy of the nerve fiber and retinal ganglion cell layers and optic nerves was present. Results of electron microscopic examination demonstrated 1.2 microns electron-dense, double-membrane-bound inclusions, consisting of calcium by electron-probe analysis, in retinal ganglion cells. The optic nerve was homoplasmic for mutations 4160 and 14484. CONCLUSION: Optic nerve and inner retinal atrophy in LHON may be a result of metabolic mitochondrial dysfunction leading to intramitochondrial calcification. Homoplasmy for mitochondrial mutations 4160 and 14484 in the leukocyte/platelet fraction of whole blood may correlate with homoplasmy in the optic nerve.     

Late onset dysthyroid optic neuropathy

We report three rare occurrences of late onset dysthyroid optic neuropathy. We reviewed each case in detail and found that these middle-aged patients developed onset of optic neuropathy 7 to 12 years following stabilization of clinically significant, stable ophthalmopathy. There was no corresponding reactivation of orbital inflammatory symptoms or signs. Characteristic of a Graves' ophthalmopathy, the vision was responsive to either corticosteroid or surgical decompression, or to a combination thereof. None of the patients had diabetes, hypertensive, or cardiovascular disease. We hypothesize that in these unique cases possible mechanical vascular factors may have induced decompensation of optic nerve function in otherwise stable disease.     

Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage

Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations. Three LHON mtDNA mutations at nucleotide positions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus designated as "primary" LHON mutations. Fifteen other "secondary" LHON mtDNA mutations have been identified, but their pathogenicity is unclear. mtDNA haplotype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and controls has shown that, unlike the 3460 and 11778 mutations, which are distributed throughout the European-derived (Caucasian) mtDNA phylogeny, patients containing the 14484 mutation tended to be associated with European mtDNA haplotype J. To investigate this apparent clustering, we performed chi2-based statistical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree. Our results indicate that, unlike the 3460 and 11778 mutations, the 14484 mutation was not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was next shown to occur on the haplogroup J background more frequently that expected, consistent with the observation that approximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation also exhibited a moderate clustering on haplogroup J. These observations were supported by statistical analysis using all available mutation frequencies reported in the literature. This paper thus illustrates the potential importance of genetic background in certain mtDNA-based diseases, speculates on a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases.     

Magnetic resonance imaging in optic neuropathy

Magnetic resonance imaging has revolutionised the ability to investigate intrinsic disease of the anterior optic pathways. We review the data accumulated from this technique not only in the conditions, such as neoplasia, which have traditionally been the domain of neuroimaging, but also in inflammatory, metabolic and degenerative diseases.     

Radiation optic neuropathy after stereotactic radiosurgery

PURPOSE: The purpose of the study is to report the occurrence of optic neuropathy after stereotactic radiosurgery for perichiasmal tumors. METHODS: Records of four patients with visual deterioration after stereotactic radiosurgery were reviewed, including clinical findings, neuroimaging results, and treatment methods. RESULTS: Optic neuropathy developed 7 to 30 months after gamma knife radiosurgery. All patients experienced an abrupt change in visual function. Clinical findings indicated anterior visual pathway involvement. Patterns of field loss included nerve fiber bundle and homonymous hemianopic defects. Gadolinium-enhanced magnetic resonance imaging (MRI) showed swelling and enhancement of the affected portion of the visual apparatus in three patients. Systemic corticosteroids were administered in all patients and one partially recovered. One patient also received hyperbaric oxygen without improvement. CONCLUSIONS: Although rare, optic neuropathy may follow radiosurgery to lesions near the visual pathways. Careful dose planning guided by MRI with restriction of the maximal dose to the visual pathways to less than 8 Gy will likely reduce the incidence of this complication.     

Neural network differentiation of optic neuritis and anterior ischaemic optic neuropathy

AIMS: The efficacy of an artificial intelligence technique, neural network analysis, was examined in differentiating two optic neuropathies with overlapping clinical profiles-idiopathic optic neuritis (ON) and non-arteritic anterior ischaemic optic neuropathy (AION). METHODS: A neural network was trained with data from 116 patients with 'gold standard' diagnoses of ON or AION. It was then tested with data from 128 patients with presumed ON or AION, and the correlation of the network's diagnosis with that of expert clinicians tabulated. RESULTS: The network agreed with the clinicians on 97.8% (88 of 90) of the patients with presumed ON and 94.7% (36 of 38) of the patients with presumed AION. Youth, female sex, better initial acuity, a central scotoma, subsequent improvement in acuity, or progressive disease biased the network towards a diagnosis of ON, while advanced age, male sex, presence of hypertension, poor initial acuity, an altitudinal field defect, disc oedema, or less improvement in acuity biased the network towards a diagnosis of AION. CONCLUSION: Neural network analysis is a useful technique for classification of optic neuropathies, particularly where there is overlap of clinical findings.     

Luxury perfusion following anterior ischemic optic neuropathy

To study the role of adenosine in sleep regulation, the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the antagonist caffeine were administered to rats. Intraperitoneal (i.p.) CPA 1 mg/kg but not 0.1 mg/kg, suppressed rapid-eye-movement (REM) sleep and enhanced electroencephalographic (EEG) slow-wave activity (power density 0.75-4.0 Hz) in non-REM sleep. The latter effect was remarkably similar to the response to 6-h sleep deprivation. The effects persisted when CPA-induced hypothermia was prevented. Caffeine (10 and 15 mg/kg i.p.) elicited a dose-dependent increase in waking followed by a prolonged increase of slow-wave activity in non-REM sleep. The combination of caffeine (15 mg/kg) and sleep deprivation caused less increase in slow-wave activity than sleep deprivation alone, indicating that caffeine may reduce the buildup of sleep pressure during waking. The results are consistent with the involvement of adenosine in the regulation of non-REM sleep.     

Potential neuroprotective therapy for glaucomatous optic neuropathy

Although mexiletine, an antiarrhythmic with local anesthetic properties, has been reported to relieve discomfort in diabetic neuropathy, its usefulness in the treatment of HIV-related painful peripheral neuropathy (PPN) has not been determined. The tolerance and effectiveness of mexiletine in HIV-related PPN were assessed in 22 patients who were randomized to receive mexiletine (maximum dose, 600 mg/day) or placebo for 6 weeks, followed by the alternative intervention for 6 weeks after a 1-week washout period. The daily pain response was assessed using a visual analogue scale card in 19 patients who received at least 2 weeks of the drug, 16 of whom were crossed-over to receive the alternate agent. No statistically significant difference was found between the mean daily pain scores for patients receiving mexiletine versus placebo, irrespective of the order in which the agents were received. Comparing the mean individual daily pain scores for each phase of study, 5 patients (31%) had significantly less pain while receiving mexiletine compared with their response to placebo, 5 patients (31%) had significantly less pain while receiving placebo, and no difference was noted in 6 patients (38%). Crossover and multivariate analyses for repeated measures showed no apparent difference in the response to mexiletine versus placebo. Dose-limiting adverse events occurred in 39% of those receiving mexiletine, but only 1 patient (5%) discontinued placebo. Mexiletine was only modestly well tolerated despite its relatively brief period of administration, and no evidence was found to support its benefit in HIV-related PPN. Although a first-drug effect was not demonstrated, a powerful placebo effect was seen in some patients.     

Posterior ischemic optic neuropathy associated with migraine

The Foot Function Index is a validated and reliable instrument for measuring foot pain, disability, and activity restriction in patients with rheumatoid arthritis. For the purposes of orthopaedic studies in which one foot serves as an internal control, we assessed the side-to-side reliability of the seven-question Foot Function Index pain subscale. Thirty patients with rheumatoid arthritis completed visual analog scale pain questionnaires for both feet on two occasions 8 days apart. Internal reliability of the scale was high, with Cronbach's alphas ranging from 0.94 to 0.96, suggesting good left versus right discriminatory abilities. Principal component factor analysis segregated the questions into two large clusters containing predominantly either left or right foot items. Intraclass correlation coefficients were examined for test-retest reliability (separated by side) and for side-to-side reliability (separated by the day of test). The resultant intraclass correlation coefficients were nearly equivalent, ranging from 0.79 to 0.89. Generalizability analysis yielded similar results. Intraclass correlation coefficients and generalizability analysis demonstrate that the majority of variation is best explained by the differences within subjects or between subjects rather than by test-retest or side-to-side differences. We recommend the Foot Function Index as a reliable measurement scale for use in orthopaedic interventional trials.