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BACKGROUND: To quantify the degree of ganglion cell degeneration through spectral domain optical coherence tomography (SD-OCT) in adult patients with post-stroke homonymous visual field defect. METHODS: Fifty patients with acquired visual field defect due to stroke (mean age = 61 years) and thirty healthy controls (mean age = 58 years) were included. Mean deviation (MD) and pattern standard deviation (PSD), average peripapillary retinal nerve fibre layer thickness (pRNLF-AVG), average ganglion cell complex thickness (GCC-AVG), global loss volume (GLV) and focal loss volume (FLV) were measured. Patients were divided according to the damaged vascular territories (occipital vs. parieto-occipital) and stroke type (ischaemic vs. haemorrhagic). Group analysis was conducted with ANOVA and multiple regressions. RESULTS: pRNFL-AVG was significantly decreased among patients with lesions in parieto-occipital territories compared to controls and to patients with lesions in occipital territories (p = .04), with no differences with respect to stroke type. GCC-AVG, GLV and FLV differed in stroke patients and controls, regardless of stroke type and involved vascular territories. Age and elapsed time from stroke had a significant effect on pRNFL-AVG and GCC-AVG (p < .01), but not on MD and PSD. CONCLUSIONS: Reduction of SD-OCT parameters occurs following both ischaemic and haemorrhagic occipital stroke, but it is larger when the injury extends to parietal territories and increases as time since stroke increases. The size of visual field defect is unrelated to SD-OCT measurements. Macular GCC thinning appeared to be more sensitive than pRNFL in detecting retrograde retinal ganglion cell degeneration and its retinotopic pattern in stroke.
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Células Ganglionares de la Retina , Accidente Cerebrovascular , Adulto , Humanos , Persona de Mediana Edad , Células Ganglionares de la Retina/patología , Campos Visuales , Fibras Nerviosas/patología , Retina , Trastornos de la Visión , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/patología , Tomografía de Coherencia Óptica/métodosRESUMEN
OBJECTIVE: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. METHODS: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. RESULTS: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. INTERPRETATION: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.
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Proteasas ATP-Dependientes/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , GTP Fosfohidrolasas/genética , Atrofia Óptica/genética , Enfermedades del Nervio Óptico/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients. METHODS: In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions. RESULTS: In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (p ≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (p < 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8-48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula. CONCLUSIONS: In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations.
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Adrenoleucodistrofia , Tomografía de Coherencia Óptica , Adrenoleucodistrofia/diagnóstico por imagen , Adulto , Estudios Transversales , Humanos , Estudios Longitudinales , Masculino , Fibras Nerviosas , Células Ganglionares de la RetinaRESUMEN
We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult-onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39-year-old male with a 9-year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin-gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy.
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Amiloidosis Familiar/complicaciones , Amiloidosis Familiar/genética , Parálisis Facial/etiología , Gelsolina/genética , Mutación/genética , Adulto , Progresión de la Enfermedad , Salud de la Familia , Humanos , MasculinoRESUMEN
It is widely known that visuospatial neglect and hemianopia maybe superimposed. We considered the differences in implicit information processing which is effective in patients with neglect but not with hemianopia. We then hypothesize that a prime-word in the neglected field should determine a semantic activation effect but not in a blind hemifield. Moreover eye movements could provide further details. In this work we considered a patient with a bilateral with the presence of either a left visual neglect and a right homonymous hemianopia. Our results supported implicit information processing in the space affected by neglect but not by hemianopia.
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Introduction: Homonymous visual field defects (HVFDs) following acquired brain lesions affect independent living by hampering several activities of everyday life. Available treatments are intensive and week- or month-long. Transcranial Direct current stimulation (tDCS), a plasticity-modulating non-invasive brain stimulation technique, could be combined with behavioral trainings to boost their efficacy or reduce treatment duration. Some promising attempts have been made pairing occipital tDCS with visual restitution training, however less is knows about which area/network should be best stimulated in association with compensatory approaches, aimed at improving exploratory abilities, such as multisensory trainings. Methods: In a proof-of-principle, sham-controlled, single-blind study, 15 participants with chronic HVFDs underwent four one-shot sessions of active or sham anodal tDCS applied over the ipsilesional occipital cortex, the ipsilesional or contralesional posterior parietal cortex. tDCS was delivered during a compensatory multisensory (audiovisual) training. Before and immediately after each tDCS session, participants carried out a visual detection task, and two visual search tasks (EF and Triangles search tests). Accuracy (ACC) and response times (RTs) were analyzed with generalized mixed models. We investigated differences in baseline performance, clinical-demographic and lesion factors between tDCS responders and non-responders, based on post-tDCS behavioral improvements. Lastly, we conducted exploratory analyses to compare left and right brain-damaged participants. Results: RTs improved after active ipsilesional occipital and parietal tDCS in the visual search tasks, while no changes in ACC were detected. Responders to ipsilesional occipital tDCS (Triangle task) had shorter disease duration and smaller lesions of the parietal cortex and the superior longitudinal fasciculus. On the other end, on the EF test, those participants with larger damage of the temporo-parietal cortex or the fronto-occipital white matter tracts showed a larger benefit from contralesional parietal tDCS. Overall, the visual search RTs improvements were larger in participants with right-sided hemispheric lesions. Conclusion: The present result shows the facilitatory effects of occipital and parietal tDCS combined with compensatory multisensory training on visual field exploration in HVFDs, suggesting a potential for the development of new neuromodulation treatments to improve visual scanning behavior in brain-injured patients.
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AIMS: Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy and are currently poorly studied. We designed an eye-tracking-based test to evaluate oculomotor function in patients with type 1 diabetes. METHODS: We used the SRLab-Tobii TX300 Eye tracker®, an eye-tracking device, coupled with software that we developed to test abnormalities in the oculomotor system. The software consists of a series of eye-tracking tasks divided into 4 classes of parameters (Resistance, Wideness, Pursuit and Velocity) to evaluate both smooth and saccadic movement in different directions. We analyzed the oculomotor system in 34 healthy volunteers and in 34 patients with long-standing type 1 diabetes. RESULTS: Among the 474 parameters analyzed with the eye-tracking-based system, 11% were significantly altered in patients with type 1 diabetes (p < 0.05), with a higher proportion of abnormalities observed in the Wideness (24%) and Resistance (10%) parameters. Patients with type 1 diabetes without diabetic neuropathy showed more frequently anomalous measurements in the Resistance class (p = 0.02). The classes of Velocity and Pursuit were less frequently altered in patients with type 1 diabetes as compared to healthy subjects, with anomalous measurements mainly observed in patients with diabetic neuropathy. CONCLUSIONS: Abnormalities in oculomotor system function can be detected in patients with type 1 diabetes using a novel eye-tracking-based test. A larger cohort study may further determine thresholds of normality and validate whether eye-tracking can be used to non-invasively characterize early signs of diabetic neuropathy. TRIAL: NCT04608890.
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Diabetes Mellitus Tipo 1 , Neuropatías Diabéticas , Estudios de Cohortes , Diabetes Mellitus Tipo 1/complicaciones , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Humanos , Seguimiento Ocular Uniforme , Movimientos SacádicosRESUMEN
Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.
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BACKGROUND: Idiopathic Intracranial Hypertension (IIH) diagnosis requires lumbar puncture to measure cerebrospinal fluid (CSF) pressure. The Pre-Lumbar puncture Intracranial Hypertension Scale (PLIHS) is aimed to detect cases that will show raised or normal CSF opening pressure. METHODS: Retrospective analysis of records of patients who underwent lumbar puncture for suspect IIH. The target was CSF opening pressure ≥ 250 mmH2O, whereas a set of known neurological, neuro-ophthalmological and neuro-radiological parameters, plus obesity, were used as predictors in a logistic regression model. The PLIHS was based on significant predictors and a cut-off was validated using chi-squared test around CSF opening pressure ≥ 250 and < 200 mmH2O. RESULTS: Records of 162 patients were included: CSF opening pressure was <200 mmH2O in 40 and ≥ 250 mmH2O in 95 patients; 85 fulfilled IIH diagnosis. PLIHS is based on Frisén grade 2 or higher papilledema, tinnitus, empty sella, perioptic subarachnoid space distension, and obesity. Score range is 0-7: correlation with CSF opening pressure is 0.508 (p < .001), and PLIHS score is different between subjects not diagnosed with IIH, and those diagnosed with IIH both with and without papilledema (p < .001). PLIHS score ≤ 2 identifies cerebrospinal fluid pressure < 200 mmH2O; PLIHS score ≥ 3 identifies CSF opening pressure ≥ 250 mmH2O, IIH diagnosis, visual acuity ≤0.7, and optic nerve atrophy. CONCLUSIONS: The PLIHS, can be used to identify patients who will particularly need LP, thus helping with the organization of the diagnostic work-up by optimising healthcare resources and potentially limit the likelihood to incur in LP-related adverse events.
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Hipertensión Intracraneal , Seudotumor Cerebral , Presión del Líquido Cefalorraquídeo , Humanos , Hipertensión Intracraneal/diagnóstico , Presión Intracraneal , Seudotumor Cerebral/complicaciones , Seudotumor Cerebral/diagnóstico , Estudios Retrospectivos , Punción EspinalRESUMEN
Patients with Leber's hereditary optic neuropathy (LHON) have loss of central vision with severe damage of small-caliber fibers of the papillomacular bundle and optic nerve atrophy. The aim of this study was to define the presence and topographical distribution of brain grey matter (GM) and white matter (WM) injury in LHON patients using voxel-based morphometry (VBM). The correlation of such changes with neuro-ophthalmologic findings and measurements of peripapillary retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) was also assessed. Dual-echo and fast-field echo scans were acquired from 12 LHON patients and 12 matched controls. VBM analysis was performed using SPM5 and an ANCOVA model. A complete neuro-ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary RNFL thickness measurements were obtained in all the patients. Compared with controls, average peripapillary RNFL thickness was significantly decreased in LHON patients. LHON patients also had significant reduced GM volume in the bilateral primary visual cortex, and reduced WM volume in the optic chiasm, optic tract, and several areas located in the optic radiations (OR), bilaterally. Visual cortex and OR atrophy were significantly correlated with average and temporal peripapillary RNFL thickness (P < 0.001; r values ranging from 0.76 to 0.89). Brain damage in patients with LHON is not limited to the anterior visual pathways, but extends posteriorly to the OR and the primary visual cortex. Such a damage to the posterior parts of the visual pathways may be due either to trans-synaptic degeneration secondary to neuroaxonal damage in the retina and optic nerve or to local mitochondrial dysfunction.
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Atrofia Óptica Hereditaria de Leber/patología , Nervio Óptico/patología , Retina/patología , Corteza Visual/patología , Vías Visuales/patología , Adulto , Atrofia , Mapeo Encefálico/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Atrofia Óptica Hereditaria de Leber/diagnóstico , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
Non-organic vision loss (NOVL), a functional partial or global vision loss, might be considered a manifestation of conversion disorder. The few previous studies focused on investigating the relationship between cerebral activity and subjective symptoms in NOVL; however, the emotional processing is still neglected. In the present case-controls study, we investigated the capability of two individuals diagnosed with NOVL to recognize implicitly the emotions of fear and anger; this was assessed through a facial emotion recognition task based on the redundant target effect. In addition, the level of alexithymia was measured by asking them to judge explicitly their ability to identify and describe emotions. Both individuals showed selective difficulties in recognizing the emotion of fear when their performance was contrasted with a matched control sample; they also mislabeled other emotional stimuli, judging them as fearful, when they were not. However, they did not report alexithymia when measured using a standard questionnaire. This preliminary investigation reports a mismatch between the implicit (i.e., the behavior in the experimental paradigm) and the explicit (i.e., the subjective evaluation of one's own emotional capability) components of the emotional processing in NOVL. Moreover, fear seems to represent a critical emotion in this condition, as has been reported in other psychiatric disorders. However, possible difficulties in the emotional processing of fear would emerge only when they are inferred from an implicit behavior, instead of a subjective evaluation of one's own emotional processing capability.