The Pattern of Retinal Ganglion Cell Loss in OPA1-Related Autosomal Dominant Optic Atrophy Inferred From Temporal, Spatial, and Chromatic Sensitivity Losses

PURPOSE. Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC subtypes. METHODS. We recruited 25 patients carrying pathogenic OPA1 mutations and age-matched healthy individuals. Spatial contrast sensitivity functions (SCSFs) and chromatic contrast sensitivity were quantified, the latter using the Cambridge Colour Test. In 11 patients, long (L) and short (S) wavelength-sensitive cone temporal acuities were measured as a function of target illuminance, and L-cone temporal contrast sensitivity (TCSF) as a function of temporal frequency. RESULTS. Spatial contrast sensitivity functions were abnormal, with the loss of sensitivity increasing with spatial frequency. Further, the highest L-cone temporal acuity fell on average by 10 Hz and the TCSFs by 0.66 log(10) unit. Chromatic thresholds along the protan, deutan, and tritan axes were 8, 9, and 14 times higher than normal, respectively, with losses increasing with age and S-cone temporal acuity showing the most significant age-related decline. CONCLUSIONS. Losses of midget parvocellular, parasol magnocellular, and bistratified koniocellular RGCs could account for the losses of high spatial frequency sensitivity and protan and deutan sensitivities, high temporal frequency sensitivity, and S-cone temporal and tritan sensitivities, respectively. The S-cone-related losses showed a significant deterioration with increasing patient age and could therefore prove useful biomarkers of disease progression in DOA.Peer reviewe

Childhood-onset Leber hereditary optic neuropathy

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C. RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye. CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor

Use of antihypertensive medication after ischemic stroke in young adults and its association with long-term outcome

Background: Knowledge on the use of secondary preventive medication in young adults is limited. Methods: We included 936 first-ever ischemic stroke 30-day survivors aged 15-49, enrolled in the Helsinki Young Stroke Registry, 1994-2007. Follow-up data until 2012 came from Finnish Care Register, Statistics Finland, and Social Insurance Institution of Finland. Usage thresholds were defined as non-users, low (prescription coverage 80%). Adjusted Cox regression allowed assessing the association of usage with all-cause mortality and recurrent vascular events. Results: Of our patients, 40.5% were non-users, 7.8% had low usage, 11.8% intermediate usage and 40.0% high usage. Median follow-up was 8.3 years. Compared to non-users, risk of mortality and recurrent stroke or TIA was lower for patients with low-intermediate (HR 0.40, 95% CI 0.22-0.65; HR 0.31, 95% CI 0.18-0.53) and high usage (HR 0.25, 95% CI 0.15-0.42; HR 0.30, 95% CI 0.19-0.46), after adjustment for confounders. Conclusions: Use of antihypertensives was suboptimal in one-third of patients in whom antihypertensives were initially prescribed. Users were at lower risk of mortality and recurrent stroke or TIA compared to non-users.Key Messages The use of antihypertensive medication is suboptimal in one-third of patients in whom antihypertensive medication was initially prescribed after ischemic stroke at young age. The risk of mortality and recurrent stroke or TIA is lower for users of antihypertensive medication after ischemic stroke at young age compared to non-users, after adjustment for relevant confounders including pre-existing hypertension and prior use of antihypertensive medication. Specific guidelines on antihypertensive medication use after ischemic stroke at young age are lacking. However, our results may motivate doctors and patients in gaining better usage of antihypertensive medication, since better usage was associated with more favorable outcome in this study.Peer reviewe

Cluster analysis to estimate the risk of preeclampsia in the high-risk Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study

Objectives Preeclampsia is divided into early-onset (delivery before 34 weeks of gestation) and late-onset (delivery at or after 34 weeks) subtypes, which may rise from different etiopathogenic backgrounds. Early-onset disease is associated with placental dysfunction. Late-onset disease develops predominantly due to metabolic disturbances, obesity, diabetes, lipid dysfunction, and inflammation, which affect endothelial function. Our aim was to use cluster analysis to investigate clinical factors predicting the onset and severity of preeclampsia in a cohort of women with known clinical risk factors. Methods We recruited 903 pregnant women with risk factors for preeclampsia at gestational weeks 12(+0)-13(+6). Each individual outcome diagnosis was independently verified from medical records. We applied a Bayesian clustering algorithm to classify the study participants to clusters based on their particular risk factor combination. For each cluster, we computed the risk ratio of each disease outcome, relative to the risk in the general population. Results The risk of preeclampsia increased exponentially with respect to the number of risk factors. Our analysis revealed 25 number of clusters. Preeclampsia in a previous pregnancy (n = 138) increased the risk of preeclampsia 8.1 fold (95% confidence interval (CI) 5.711.2) compared to a general population of pregnant women. Having a small for gestational age infant (n = 57) in a previous pregnancy increased the risk of early-onset preeclampsia 17.5 fold (95%CI 2.160.5). Cluster of those two risk factors together (n = 21) increased the risk of severe preeclampsia to 23.8-fold (95%CI 5.160.6), intermediate onset (delivery between 34(+0)-36(+6) weeks of gestation) to 25.1-fold (95%CI 3.179.9) and preterm preeclampsia (delivery before 37(+0) weeks of gestation) to 16.4-fold (95%CI 2.052.4). Body mass index over 30 kg/m(2) (n = 228) as a sole risk factor increased the risk of preeclampsia to 2.1-fold (95%CI 1.13.6). Together with preeclampsia in an earlier pregnancy the risk increased to 11.4 (95%CI 4.520.9). Chronic hypertension (n = 60) increased the risk of preeclampsia 5.3-fold (95%CI 2.49.8), of severe preeclampsia 22.2-fold (95%CI 9.941.0), and risk of early-onset preeclampsia 16.7-fold (95%CI 2.057.6). If a woman had chronic hypertension combined with obesity, gestational diabetes and earlier preeclampsia, the risk of term preeclampsia increased 4.8-fold (95%CI 0.121.7). Women with type 1 diabetes mellitus had a high risk of all subgroups of preeclampsia. Conclusion The risk of preeclampsia increases exponentially with respect to the number of risk factors. Early-onset preeclampsia and severe preeclampsia have different risk profile from term preeclampsia.Peer reviewe

Childhood-onset Leber hereditary optic neuropathy

Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m. 3460G>A, m. 11778G>A or m. 14484T>C. Results In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m. 3460G>A and m. 14484T>C mutations compared with the m. 11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) >= 0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA Conclusions Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.Peer reviewe

Nuoren aivoinfarktipotilaan erityispiirteet

English summaryPeer reviewe

Cancer and stroke : commonly encountered by clinicians, but little evidence to guide clinical approach

The association between stroke and cancer is well-established. Because of an aging population and longer survival rates, the frequency of synchronous stroke and cancer will become even more common. Different pathophysiologic mechanisms have been proposed how cancer or cancer treatment directly or via coagulation disturbances can mediate stroke. Increased serum levels of D-dimer, fibrin degradation products, and CRP are more often seen in stroke with concomitant cancer, and the clot retrieved during thrombectomy has a more fibrin- and platelet-rich constitution compared with that of atherosclerotic etiology. Multiple infarctions are more common in patients with active cancer compared with those without a cancer diagnosis. New MRI techniques may help in detecting typical patterns seen in the presence of a concomitant cancer. In ischemic stroke patients, a newly published cancer probability score can help clinicians in their decision-making when to suspect an underlying malignancy in a stroke patient and to start cancer-screening studies. Treating stroke patients with synchronous cancer can be a delicate matter. Limited evidence suggests that administration of intravenous thrombolysis appears safe in non-axial intracranial and non-metastatic cancer patients. Endovascular thrombectomy is probably rather safe in these patients, but probably futile in most patients placed on palliative care due to their advanced disease. In this topical review, we discuss the epidemiology, pathophysiology, and prognosis of ischemic and hemorrhagic strokes as well as cerebral venous thrombosis and concomitant cancer. We further summarize the current evidence on acute management and secondary preventive therapy.Peer reviewe

Clinical utility gene card for : inherited optic neuropathies including next-generation sequencing-based approaches

Non peer reviewe

WFS1-Associated Optic Neuropathy : Genotype-Phenotype Correlations and Disease Progression

center dot OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON).center dot DESIGN: Multicenter cohort study. center dot METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. Main Outcome Measures: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile.center dot RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. center dot CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON. (Am J Ophthalmol 2022;241: 927. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))Peer reviewe