RESUMO
Styloidogenic jugular venous compression syndrome has been recently described as a new cause of idiopathic intracranial hypertension. We present a 69-year-old patient, without other relevant medical history, presenting with 3 years of positional headache associated with decreased vision when reading and while turning her head to the right or left. She also reported pulsatile low-frequency tinnitus. Papilloedema was noted on the physical examination and, on imaging, an enlarged styloid process that induced jugular vein compression. The patient underwent styloidectomy with resolution of her symptoms and normalisation of her visual fields.
RESUMO
PURPOSE: To determine normative values, intra- and inter-session variability for a range of parameters derived from the photopic negative response (PhNR) using a handheld mini-Ganzfeld stimulator in healthy normal adults. METHODS: Light-adapted flash full-field electroretinograms (ERGs) were recorded from healthy individuals with no visual complaints, visual acuity equal to or better than 0.0 logMAR (20/20 Snellen), and negative family history for visual diseases. ERGs were recorded from both eyes using a DTL® type fiber electrode after dilation of the pupils with instillation of 1 drop of tropicamide eye drops (1%). The full-field PhNR stimulus conditions were produced by a LED-based ColorBurst™ (Diagnosys LLC, Lowell, MA, USA) handheld stimulator. Red flashes of 1, 5 and 7 cd.s/m2 on a blue background of 10 cd/m2 were presented. A-wave, b-wave and PhNR amplitude (determined by both baseline to trough-BT and peak to trough-PT) and peak times were analyzed. Normal limits were determined as 5% percentile for amplitudes and 95% percentile for latencies. Intra- and inter-session variability were assessed with Wilcoxon signed-rank test, intraclass correlation coefficient (ICC) and the coefficient of variability (COV). RESULTS: Normative limits for PhNR amplitude (µV) using 1, 5 and 7 cd.s./m2 stimuli were, respectively: 20.81; 18.06 and 19.60 for BT and 69.11; 77.98; 76.51 for PT. Peak times (ms) normative limits for 1, 5 and 7 cd.s/m2 intensities were, respectively, 65.98; 78.20 and 77.96. Overall, intra-session variability assessed by coefficients of variation ranged from 1.35 to 10.28%. Inter-session variability disclosed significant intraclass correlation values for all PhNR parameters only for 1 cd.s/m2 stimuli. CONCLUSIONS: The normative values provided by this study are clinically helpful in the diagnosis of inner retinal disorders, especially those affecting retinal ganglion cells such as glaucoma and other optic neuropathies. Further studies, including a larger sample with variable age range would extend the validity of the current results.
Assuntos
Visão de Cores/fisiologia , Eletrorretinografia/métodos , Retina/fisiologia , Adolescente , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Microeletrodos , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estimulação Luminosa , Valores de Referência , Células Ganglionares da Retina/fisiologia , Adulto JovemRESUMO
The main objective of this study was to evaluate the retinas of severely or critically ill COVID-19 patients during their hospital stay, at varying time points after symptoms onset. This was a case series observed during May 2020 in two referral centers for COVID-19 treatment in Rio de Janeiro, Brazil. 47 eyes from 25 hospitalized patients with severe or critical confirmed illness were evaluated. A handheld retinal camera was used to acquire bilateral fundus images at several time points after symptoms onset. Electronic health records were retrospectively analyzed and clinical data collected. Severe and critical diseases were noticed in 52% (13/25) and 48% (12/25) of enrolled patients, respectively. Retinal changes were present in 12% (3/25) of patients: a 35 year-old male demonstrated bilateral nerve fiber layer infarcts and microhemorrhages in the papillomacular bundle, but required mechanical ventilation and developed severe anemia and systemic hypotension, acute kidney injury and neurologic symptoms during the course of the disease (critical illness); a 56 year-old male, who required full enoxaparin anticoagulation due to particularly elevated D-dimer (>5.0 mcg/mL), demonstrated unilateral and isolated flame-shaped hemorrhages; and a 49 year-old hypertensive male showed bilateral and discrete retinal dot and blot microhemorrhages. The other 22 patients evaluated did not demonstrate convincing retinal changes upon examination. There was no correlation between disease severity and admission serum levels of CRP, D-dimer and ferritin. This was the first study to show that vascular retinal changes may be present in not insignificant numbers of severe or critical COVID-19 inpatients. These retinal changes, only seen after morbid developments, were likely secondary to clinical intercurrences or comorbidities instead of a direct damage by SARS-CoV-2, and may be important and easily accessible outcome measures of therapeutic interventions and sentinels of neurologic and systemic diseases during COVID-19 pandemic.
Assuntos
COVID-19/complicações , Hemorragia Retiniana/epidemiologia , Adulto , Idoso , COVID-19/patologia , Feminino , Fundo de Olho , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/patologia , Vasos Retinianos/patologiaRESUMO
Purpose: The photopic negative response (PhNR) is an electrophysiological method that provides retinal ganglion cell function assessment using full-field stimulation that does not require clear optics or refractive correction. The purpose of this study was to assess ganglion cell function by PhNR in affected and asymptomatic carriers from Brazilian families with LHON. Methods: Individuals either under suspicion or previously diagnosed with LHON and their family members were invited to participate in this cross-sectional study. Screening for the most frequent LHON mtDNA mutations was performed. Visual acuity, color discrimination, visual fields, pattern-reversal visual evoked potentials (PRVEP), full-field electroretinography and PhNR were tested. A control group of healthy subjects was included. Full-field ERG PhNR were recorded using red (640 nm) flashes at 1 cd.s/m2, on blue (470 nm) rod saturating background. PhNR amplitude (µV) was measured using baseline-to-trough (BT). Optical coherence tomography scans of both the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were measured. PhNR amplitudes among affected, carriers and controls were compared by Kruskal-Wallis test followed by post-hoc Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation. Results: Participants were 24 LHON affected patients (23 males, mean age=30.5 ± 11.4 yrs) from 19 families with the following genotype: m.11778G>A [N = 15 (62%), 14 males]; m.14484T>C [N = 5 (21%), all males] and m.3460G>A [N = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A (N = 11); m.3460G>A (N = 2) and m.14484T>C (N = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced (p = 0.0001) in LHON affected (-5.96 ± 3.37 µV) compared to carriers (-16.53 ± 3.40 µV) and controls (-23.91 ± 4.83; p < 0.0001) and in carriers compared to controls (p = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness (r = -0.62, p < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers. Conclusions: In this cohort of Brazilian families with LHON the photopic negative response was severely reduced in affected patients and mildly reduced in asymptomatic carriers suggesting possible subclinical abnormalities in the latter. These findings were similar among pathogenic mutations.
RESUMO
From 1991 to 1993, an epidemic of optic and peripheral neuropathy-the largest of the century-broke out in Cuba, affecting more than 50,000 people. Initially the main clinical features were decreased visual acuity, central and cecocentral scotomas, impaired color vision and absence of the papillomacular bundle. Later, peripheral and mixed optic-peripheral forms began to appear. Due to the magnitude of the epidemic, the Cuban government requested help from the international community at the 46th World Health Assembly in 1993. PAHO and WHO immediately responded by sending a mission of international experts. Several hypotheses regarding the pathogenesis of Cuban epidemic neuropathy were put forward including: toxic, nutritional, genetic and infectious. The authors refer to extensive studies by researchers sponsored by the Cuban government and PAHO/WHO, joined by scientists from several other countries, including the USA. This paper describes their multidisciplinary work, particularly devoted to investigating the hypothesis of a primary toxic-nutritional cause of the epidemic. Clinical aspects, such as case definition and clinical description, were vital issues from the start. Cuban physicians who first examined patients received a clear impression of its toxic-nutritional origin, later confirmed by international experts. Research then focused on the mechanisms contributing to damage under the toxic-nutritional hypothesis. These included injuries to the mitochondrial oxidative phosphorylation pathway, nutritional deficiencies, excitotoxicity, formate toxicity and dysfunction of the blood-brain barrier. It was expected that the results of such international collaboration into this major health problem would also shed more light on mechanisms underlying other nutritional or tropical myeloneuropathies. KEYWORDS Optic neuritis, optic neuropathy, peripheral neuropathy, neurotoxicity syndromes, disease outbreaks, international cooperation, Cuba Erratum: Page 30, first complete paragraph, line 7, "Two models were developed independently by Cuban researchers" should read "Two models were developed independently by AAS and AGQ."
Assuntos
Processos Grupais , Doenças do Nervo Óptico/epidemiologia , Doenças do Nervo Óptico/etiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/etiologia , Cuba/epidemiologia , Surtos de Doenças , Epidemias , Abastecimento de Alimentos , Humanos , Cooperação InternacionalAssuntos
DNA Mitocondrial/genética , Micronutrientes/uso terapêutico , Doenças Mitocondriais/tratamento farmacológico , Mutação , Atrofia Óptica Hereditária de Leber/tratamento farmacológico , Ubiquinona/análogos & derivados , Criança , Humanos , Masculino , Doenças Mitocondriais/genética , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Reação em Cadeia da Polimerase , Irmãos , Resultado do Tratamento , Ubiquinona/uso terapêutico , Acuidade Visual/efeitos dos fármacos , Campos Visuais/efeitos dos fármacosRESUMO
PURPOSE: To investigate the pupillary light reflex (PLR) of patients with severe loss of vision due to Leber's Hereditary Optic Neuropathy (LHON) in the context of a proposed preservation of melanopsin-expressing retinal ganglion cells (mRGCs). METHODS: Ten LHON patients (7 males; 51.6 ± 14.1 years), with visual acuities ranging from 20/400 to hand motion perception and severe visual field losses, were tested and compared with 16 healthy subjects (7 males; 42.15 ± 15.4 years) tested as controls. PLR was measured with an eye tracker and the stimuli were controlled with a Ganzfeld system. Pupil responses were measured monocularly, to 1 second of blue (470 nm) and red (640 nm) flashes with 1, 10, 100, and 250 cd/m² luminances. The normalized amplitude of peak of the transient PLR and the amplitude of the sustained PLR at 6 seconds after the flash offset were measured. In addition, optical coherence topography (OCT) scans of the peripapillary retinal nerve fiber layer were obtained. RESULTS: The patient's peak PLR responses were on average 15% smaller than controls (P < 0.05), but 5 out of 10 patients had amplitudes within the range of controls. The patients' sustained PLRs were comparable with controls at lower flash intensities, but on average, 27% smaller to the 250 cd/m² blue light, although there was considerable overlap with the PLR amplitudes of control. All patients had severe visual field losses and the retinal nerve fiber layer thickness was reduced to a minimum around the optic disc in 8 of the 10 patients. CONCLUSIONS: The PLR is maintained overall in LHON patients despite the severity of optic atrophy. These results are consistent with previous evidence of selective preservation of mRGCs.
Assuntos
Atrofia Óptica Hereditária de Leber/fisiopatologia , Reflexo Pupilar/fisiologia , Células Ganglionares da Retina/metabolismo , Opsinas de Bastonetes/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Células Ganglionares da Retina/patologia , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: Neuron-specific enolase (NSE) is a biomarker for neuronal stress. Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease affecting retinal ganglion cells (RGC). These RGCs and their axons in the retinal nerve fiber layer (RNFL) and optic nerve head may show subclinical pathology in unaffected mutation carriers, or undergo cell death in affected patients. We hypothesize that increased levels of blood NSE may characterize LHON carriers as a biomarker of ongoing RGC stress. METHODS: Serum was obtained from 74 members of a Brazilian pedigree with LHON carrying the homoplasmic 11778/ND4 mitochondrial DNA mutation. Classified by symptoms and psychophysical metrics, 46/74 patients were unaffected mutation "carriers," 14/74 were "affected," and 14/74 were "off-pedigree" controls. Serum NSE levels were determined by ELISA specific for the γ subunit of NSE. RESULTS: Serum NSE concentrations in carriers (27.17 ± 39.82 µg/L) were significantly higher than affected (5.66 ± 4.19 µg/L; P = 0.050) and off-pedigree controls (6.20 ± 2.35 µg/L; P = 0.047). Of the 14/46 (30.4 %) carriers with significantly elevated NSE levels (mean = 75.8 ± 42.3 µg/L), 9/14 (64.3%) were male. Furthermore, NSE levels were nearly three times greater in asymptomatic male carriers (40.65 ± 51.21 µg/L) than in asymptomatic female carriers (15.85 ± 22.27 µg/L; P = 0.034). CONCLUSIONS: Serum NSE levels are higher in LHON carriers compared with affected and off-pedigree individuals. A subgroup of mostly male carriers had significantly elevated serum NSE levels. Thus, male carriers are at higher risk for LHON-related neuronal stress.
Assuntos
Doenças Assintomáticas/epidemiologia , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/metabolismo , Fosfopiruvato Hidratase/sangue , Brasil/epidemiologia , DNA Mitocondrial/genética , Saúde da Família , Feminino , Humanos , Masculino , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Fatores de Risco , Distribuição por Sexo , Estresse Fisiológico/fisiologiaRESUMO
To investigate pattern-reversal visual evoked potentials (PRVEP) in asymptomatic maternally and non-maternally related members from a large Brazilian 11778/ND4 LHON pedigree. Transient PRVEP for check sizes 15' and 60' were recorded from asymptomatic mutation carriers and non-mutant descendants of affected/non-affected males, all with best-corrected visual acuity of 20/20. A control group of spouses (off-pedigree) was also included. Parameters of N75, P100 and N135 latencies (ms) and N75-P100 peak-to-peak amplitude (µV) as well as temporal dispersion (latency of N135-latency of N75) were determined. Longitudinal testing was obtained in a subseries of carriers in three annual consecutive visits. We tested 48 asymptomatic mutation carriers, 19 descendants of affected males, 9 descendants of non-affected males and 27 off-pedigrees, all of the latter being non-mutant. All non-mutant male descendants did not differ from off-pedigree controls. Statistically prolonged P100 latencies were found in mutation carriers (P = 0.0143) when compared with off-pedigrees for check sizes 15', as well as significantly larger temporal dispersions for both check size 15' (P = 0.0012) and check size 60' (P = 0.0271). Serial testing in 15 mutation carriers disclosed prolonged P100 latencies and larger temporal dispersion that did not change over time. Subclinical PRVEP abnormalities were detected in this large group of asymptomatic carriers of the 11778/ND4 LHON mutation from the same family, confirming and extending previous psychophysical and structural findings of a selective involvement of the parvocellular pathway. PRVEP is a useful test to characterize and monitor visual dysfunction in this devastating disease.
Assuntos
Potenciais Evocados Visuais/fisiologia , Doenças Mitocondriais/fisiopatologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/fisiologia , Adolescente , Adulto , Idoso , Brasil , DNA Mitocondrial/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/genética , Mutação/genética , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Acuidade Visual/fisiologia , Adulto JovemRESUMO
PURPOSE: To study the optic nerve head (ONH) morphology of patients with Leber's hereditary optic neuropathy (LHON) in a large family from Brazil carrying the 11778/ND4 mutation and in a case series of unrelated Italian families bearing different mitochondrial DNA (mtDNA) pathogenic mutations. METHODS: Enrolled in the study were 15 LHON-affected patients (LHON-affected) and 45 LHON unaffected mutation carriers (LHON carriers) belonging to the previously reported Brazilian SOA-BR LHON pedigree and 56 LHON-affected and 101 LHON carriers from 45 unrelated LHON Italian pedigrees molecularly defined. The LHON-affected were subgrouped according to the extent of visual recovery. All individuals underwent optic nerve head (ONH) analysis by optical coherence tomography. RESULTS: In the Brazilian sample, the mean optic disc area was significantly larger in LHON carriers than in the control group (P=0.002). In the Italian sample, the mean optic disc area and vertical disc diameter were significantly higher in LHON carriers than in both LHON-affected (respectively, P=0.008 and P<0.001) and control subjects (P<0.001 in both cases). The LHON-affected with visual recovery had a significantly larger vertical disc diameter when compared with those without visual recovery (P=0.03). CONCLUSIONS: The results, revealing that the ONH size is larger in LHON carriers than in LHON-affected, suggest a protective role for this anatomic trait. Such a hypothesis is reinforced by the observation that, among the LHON-affected, larger discs correlated with visual recovery and better visual outcome. The findings may be relevant for prognosis and provide a mechanism for identifying nuclear-modifying genes implicated in the variability of penetrance in LHON.
Assuntos
Atrofia Óptica Hereditária de Leber/diagnóstico , Disco Óptico/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Análise Mutacional de DNA , DNA Mitocondrial/genética , Progressão da Doença , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Penetrância , Prognóstico , Tomografia de Coerência ÓpticaRESUMO
Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited blinding disease caused by missense mutations in the mitochondrial DNA (mtDNA). However, incomplete penetrance and a predominance of male patients presenting with vision loss suggest that modifying factors play an important role in the development of the disease. Evidence from several studies suggests that both nuclear modifier genes and environmental factors may be necessary to trigger the optic neuropathy in individuals harboring an LHON-causing mtDNA mutation. Recently, an optic neuropathy susceptibility locus at Xp21-Xq21 has been reported. In this study, we performed X-chromosomal linkage analysis in a large Brazilian family harboring a homoplasmic G11778A mtDNA mutation on a haplogroup J background. We report the identification of a novel LHON susceptibility locus on chromosome Xq25-27.2, with multipoint non-parametric linkage scores of > 5.00 (P = 0.005) and a maximum two-point non-parametric linkage score of 10.12, (P = 0.003) for marker DXS984 (Xq27.1). These results suggest genetic heterogeneity for X-linked modifiers of LHON.
Assuntos
Cromossomos Humanos X , Ligação Genética , Predisposição Genética para Doença , Atrofia Óptica Hereditária de Leber/genética , Brasil , Mapeamento Cromossômico , DNA Mitocondrial/genética , Feminino , Humanos , Masculino , Mutação , LinhagemRESUMO
PURPOSE: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease resulting in loss of central vision and dyschromatopsia, caused by mitochondrial DNA point mutations. However, only a subset of the mutation carriers becomes affected, with a higher penetrance in males. This study was conducted to investigate chromatic losses in asymptomatic carriers of the LHON mutation. METHODS: Monocular chromatic discrimination was studied with the Cambridge Colour Test (CCT; Cambridge Research Systems, Ltd., Rochester, UK) along the protan, deutan, and tritan cone isolation axes in 46 LHON carriers (15 men) belonging to the same LHON maternal lineage and 74 age-matched control subjects (39 men). Inclusion criteria were absence of ophthalmic complaints and clear ocular media. A detailed neuro-ophthalmic examination was performed in all the LHON carriers. RESULTS: The differences in threshold between carriers and control subjects were significant for the three cone isolation axes at P < 0.0001. Sixty-five percent of the carriers had abnormal protan and/or deutan thresholds; some of those with higher thresholds also had elevated tritan thresholds (13%). The male thresholds were higher and more frequent than those of the women for the protan and deutan axes (ANOVA; P < 0.05), but not for tritan thresholds. In the most severe losses, the women had instances of diffuse defect whereas all the men displayed a red-green defect. CONCLUSIONS: Male LHON asymptomatic carriers had color vision losses with the red-green pattern of dyschromatopsia typical of patients affected with LHON, which includes elevation of tritan thresholds as well. This predominantly parvocellular (red-green) impairment is compatible with the histopathology of LHON, which affects mostly the papillomacular bundle. In contrast with male losses, female losses were less frequent and severe. These gender differences are relevant to understanding LHON pathophysiology, suggesting that hormonal factors may be of great importance.
Assuntos
Defeitos da Visão Cromática/genética , DNA Mitocondrial/genética , Heterozigoto , Atrofia Óptica Hereditária de Leber/genética , Mutação Puntual , Adulto , Brasil , Testes de Percepção de Cores , Defeitos da Visão Cromática/epidemiologia , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Linhagem , Prevalência , Reprodutibilidade dos Testes , Fatores SexuaisRESUMO
PURPOSE: The authors previously presented the results of their 2001 field investigation to rural Brazil to investigate a 336-member pedigree of Leber hereditary optic neuropathy (LHON). The present work describes the yearly field investigations 2001 to 2005, utilizing a variety of highly sophisticated psychophysical and electrophysiologic procedures, in asymptomatic LHON carriers, some of whom converted to affected status. METHODS: Careful, repeated examinations of 75 carriers of homoplasmic 11778 LHON mtDNA J-haplogroup mutants were performed as part of the field investigation of this pedigree. All subjects underwent a detailed neuro-ophthalmologic investigation, including formal visual fields (Humphrey; HVF) and fundus photography. In addition, many subjects underwent rigorous psychophysical examination, including Cambridge Research Systems color vision and contrast sensitivity testing, OCT, GDx, and multifocal visual evoked response (mfVER) and multifocal electroretinogram (mfERG). Two patients followed as nonsymptomatic LHON carriers converted to affected status. RESULTS: Many LHON carriers did, in fact, show subclinical or occult abnormalities. Focal edema was often seen involving the arcuate nerve fiber bundles, and this corresponded with areas of relative paracentral or arcuate scotomas on HVF testing. Compared to controls, LHON carriers had significant losses in color vision affecting mostly the red-green system and reduction in spatial but not temporal contrast sensitivity. The mfVER and mfERG data showed that most carriers had depressed central responses and abnormal interocular asymmetries. CONCLUSIONS: In this very large pedigree of 11778 LHON, the carriers frequently showed manifestations of optic nerve impairments. Their occult disease reflected low-grade compromise that waxed and waned. In two cases, these changes led to a crescendo of dramatic impairments that characterize conversion to affected status.
Assuntos
Atrofia Óptica Hereditária de Leber/diagnóstico , Nervo Óptico/patologia , Transtornos da Visão/diagnóstico , Adolescente , Adulto , Brasil , Portador Sadio , Criança , Testes de Percepção de Cores , Sensibilidades de Contraste , DNA Mitocondrial/genética , Eletrorretinografia , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Atrofia Óptica Hereditária de Leber/genética , Disco Óptico/patologia , Linhagem , Mutação Puntual , Estudos Prospectivos , População Rural , Órgão SubcomissuralRESUMO
PURPOSE: To determine whether asymptomatic 11778 LHON carriers demonstrated impairments in (1) chromatic red/green (R/G) and blue/yellow (B/Y) contrast sensitivity functions (CSF) and in (2) luminance contrast sensitivity functions in the spatial CSF (SCSF) and temporal CSF (TCSF) domains. METHODS: Twenty-five carriers (8 male, 17 female; 34.1 +/- 15.1 years of age) of homoplasmic 11778 LHON from the same well-described family and 30 age-matched controls (17 male, 13 female; 29.2 +/- 7.1 years of age) were tested in one eye, randomly selected. Of the 25 eyes tested, 18 had normal fundus, 5 had swelling and microangiopathy, and 2 had temporal pallor. The R/G and B/Y CSFs were obtained after equiluminance correction with bichromatic horizontal sinusoidal gratings at 0.3, 0.7, and 2 cycles per degree (cpd); the SCSFs were obtained with achromatic gratings at 0.3, 2, 6, and 12 cpd; and the TCSFs were obtained at 2, 10, 20, and 33 Hz with sinusoidal modulation of a 2.7 degrees field with a superimposed spatial Gabor function. RESULTS: Differences between carriers and controls were statistically significant for all spatial frequencies of chromatic and luminance SCSFs, but not for the TCSFs. R/G equiluminance settings of carriers differed from those of controls (P < 0.001), requiring higher luminance in the green; B/Y equiluminance settings were not statistically different in carriers and controls. Fundus findings did not correlate with CS results. CONCLUSIONS: Luminance and chromatic spatial CS losses that affected all tested spatial frequencies, are reported in LHON asymptomatic carriers with the mtDNA 11778 mutation. No losses were found in the temporal CSF. An intriguing finding is that the blue system is substantially spared in this LHON family. These represent subclinical visual impairments in otherwise asymptomatic LHON carriers.
Assuntos
Percepção de Cores/fisiologia , Sensibilidades de Contraste/fisiologia , DNA Mitocondrial/genética , Mutação , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/fisiopatologia , Adolescente , Adulto , Brasil/epidemiologia , Feminino , Fusão Flicker , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/etnologia , Linhagem , Percepção Espacial , Acuidade VisualRESUMO
Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease, associated with mitochondrial DNA (mtDNA) point mutations and characterized by bilateral, usually sequential, rapid loss of central vision. The purpose of this study was to investigate electrophysiologically a small cohort of members from an extensive Brazilian family affected by LHON. Pattern-reversal visual evoked potentials (PVEP), and full-field electroretinograms (ERG) were performed on the four index members, all carrying the 11778 homoplasmic mtDNA mutation. They were a 14-year-old recently affected male, his unaffected mother, and her two affected brothers. The three affected members all had bilateral profound visual loss with visual acuities that ranged from 20/250 to CF, cecocentral defects, and severe dyschromatopsia (by FM-100). The unaffected (carrier) female had normal visual acuities, visual fields and color discrimination. Severely prolonged P100 latencies and decreased N75-P100 peak amplitudes were found in pattern-reversal VEPs for three affected members. Normal PVEP responses were found in the carrier female. Rod and cone ERG responses were normal in two affected members, but both the carrier mother and her affected son showed reduced peak-to-peak amplitude for single-flash cone response and 30 Hz flicker, with normal b-wave implicit times. Thus, optic nerve function, evaluated by PVEP, was severely reduced in LHON affected members and normal in the carrier female. However, reduced ERG cone responses suggest that LHON can also affect retinal elements, even in the absence of fundus and other clinical changes that constitute the full and classical expression of LHON.
Assuntos
Eletrorretinografia , Potenciais Evocados Visuais , Atrofia Óptica Hereditária de Leber/fisiopatologia , Adolescente , Adulto , Brasil , Estudos de Coortes , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Nervo Óptico/fisiopatologia , Linhagem , Estimulação Luminosa/métodos , Tempo de Reação , Retina/fisiopatologia , Acuidade VisualRESUMO
PURPOSE: To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial DNA (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON). DESIGN: Observational population cohort study. METHODS: A prospective investigation of an entire Brazilian LHON family. SETTING: A field investigation by an international team conducted in a remote part of Brazil. STUDY POPULATION: We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls. OBSERVATION PROCEDURES: We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis. RESULTS: We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common (P <.01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group (P <.05). CONCLUSIONS: Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.
Assuntos
Haplótipos , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/genética , Adolescente , Brasil/epidemiologia , Estudos de Coortes , Percepção de Cores , Sensibilidades de Contraste , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Fatores de Risco , Acuidade Visual , Campos VisuaisRESUMO
PURPOSE: We conducted extensive epidemiological, neuro-ophthalmological, psychophysical, and blood examinations on a newly discovered, very large pedigree with molecular analysis showing mtDNA mutation for Leber's hereditary optic neuropathy (LHON). METHODS: Four patients representing four index cases from a remote area of Brazil were sent to Sao Paulo, where complete ophthalmological examinations strongly suggested LHON. Molecular analysis of their blood demonstrated that they were LHON, homoplasmic 11778, J-haplogroup. They had an extensive family that all lived in one rural area in Brazil. To investigate this family, we drew on a number of international experts to form a team that traveled to Brazil. This field team also included several members of the Federal University of Sao Paulo, and together we evaluated 273 of the 295 family members that were still alive. We conducted epidemiological interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmological examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for both mitochondrial genetic analysis and nuclear gene linkage analysis. RESULTS: The person representing the first-generation case immigrated from Verona, Italy, to Colatina. Subsequent generations demonstrated penetrance rates of 71%, 60%, 34%, 15%, and 9%. The percentages of males were 60%, 50%, 64%, 100%, and 100%. Age at onset varied from 10 to 64 years, and current visual acuities varied from LP to 20/400. CONCLUSIONS: Almost 95% of a nearly 300-member pedigree with LHON 11778 were comprehensively studied. Analysis of environmental risk factors and a nuclear modifying factor from this group may help address the perplexing mystery of LHON: Why do only some of the genetically affected individuals manifest the disease? This fully described database may also provide an excellent opportunity for future clinical trials of any purported neuroprotective agent.