Investigation of Visual System Involvement in Spinocerebellar Ataxia Type 14.

Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear.

Self-perception and determinants of color vision in Parkinson's disease.

Visual dysfunction is common in patients with Parkinson's disease (PD). The objective of this study was to investigate the perceived impact of visual dysfunction and especially color vision loss on PD patients, and to identify retinal and disease factors associated with color vision. Thirty PD patients and thirty-four healthy controls were included. Participants performed the Farnsworth-Munsell Hue-100 test (FMT). Patients answered the National Eye Institute Visual Function Questionnaire (NEI-VFQ), Unified Parkinson's Disease Rating Scale (UPDRS) assessment, and underwent optical coherence tomography with measurement of retinal nerve fiber layer, ganglion cell layer + inner plexiform layer (GCIPL), and outer nuclear and photoreceptor layer. Dopaminergic treatment was assessed as levodopa equivalent dose (LED). Vision domains significantly worse in PD patients compared to normative data were General Vision, Near Activities, Distance Activities, Vision-Specific Dependency, Driving, and Peripheral Vision. Worse NEI-VFQ total scores were associated with worse UPDRS, higher LED, and higher age, but not with FMT, visual acuity, or OCT measures. Only two patients (7%) reported problems with color vision. In contrast, patients performed significantly worse in the FMT than healthy controls and 17 (56.7%) patients were outside the 95th percentile of normative data. In multiple regression analyses, lower LED and higher age were associated with worse color vision in the FMT. PD patients are not aware of color vision deficits. Given the impact of color vision loss on everyday tasks in other conditions, future research should investigate the impact of vision deficits on disease burden in PD.

Patients with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density.

BACKGROUND: Many studies in multiple sclerosis (MS) have investigated the retina. Little, however, is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response to environmental stimuli. OBJECTIVE: This study aims to investigate the effect of MS on corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM). METHODS: We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with cornea module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography. RESULTS: We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity but not with previous clinical trigeminal symptoms, retinal neuro-axonal damage, visual acuity or disease duration. CONCLUSION: Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.

Characterizing the phenotype of multiple sclerosis-associated depression in comparison with idiopathic major depression.

BACKGROUND: Depression is a common co-morbidity in patients with multiple sclerosis (MS). While somatic symptoms of MS correlate with depression levels, it is unclear whether the clinical presentation of MS-associated depression differs from patients with "idiopathic" major depressive disorder (MDD). OBJECTIVE: To compare the clinical phenotype of depression among MS and idiopathic MDD patients. METHODS: Mean relative contribution of individual Beck Depression Inventory-II (BDI-II) items was evaluated among n = 139 patients with relapsing-remitting MS and n = 85 MDD patients without somatic illness. Next, comparisons were repeated in n = 38 MS with clinically relevant depressive symptoms (BDI-II > 19) and n = 38 MDD patients matched for sex, age, and depression severity. Finally, the underlying construct of depression was compared across groups using confirmatory factor analysis (CFA). RESULTS: Comparisons on a whole-group level produced the expected differences along somatic/non-somatic symptoms. However, when appropriately controlling for depression severity, age, and sex, only four items contributed differentially to BDI-II total scores in MS versus MDD. CFA suggested that the underlying depression construct is essentially identical in both groups. CONCLUSION: The clinical phenotype of "idiopathic" MDD and MS-associated depression appears similar when adequately examined. The relevance of these findings for psychotherapeutic approaches for MS-associated depression should be explored in future studies.

RETINAL LESION EVOLUTION IN SUSAC SYNDROME.

PURPOSE: To describe retinal lesion development in Susac syndrome during acute, postacute, and late phases of the disease. METHODS: Cross-sectional study of four patients with Susac syndrome and longitudinal short-interval case study of one additional patient. Retinal changes were analyzed with high-resolution spectral domain optical coherence tomography and retinal fluorescein angiography. RESULTS: Retinal Susac syndrome lesions comprise four different lesion sections, which can be distinguished in acute and postacute phases of the disease: a primary section at the site of branch retinal artery occlusion, which spans more layers than supplied by the affected vessel; hypoxic sections from superficial and deep capillary networks; and an axonal damage section with degenerating axons from perished ganglion cells in the main and hypoxic sections. In the later stages, main and hypoxic lesion sections can no longer be distinguished, and both show degeneration from outer plexiform to retinal nerve fiber layers. CONCLUSION: The dynamics of lesion development and morphologically distinct lesion sections suggest more complex mechanisms of lesion evolution beyond an isolated endothelial immune reaction and subsequent hypoxic tissue damage. The characteristic lesion morphology assists in differentiating the diagnosis of acute visual loss in neuroinflammatory disease. Specificity of the identified changes has to be determined in future studies also including patients with other retinal vascular diseases.

Temporal retinal nerve fibre layer thinning in cluster headache patients detected by optical coherence tomography.

BACKGROUND: The exact pathophysiology of cluster headache (CH) is still not fully clarified. Various studies confirmed changes in ocular blood flow during CH attacks. Furthermore, vasoconstricting medication influences blood supply to the eye. We investigated the retina of CH patients for structural retinal alterations with optical coherence tomography (OCT), and how these changes correlate to headache characteristics, oxygen use and impaired visual function. METHODS: Spectral domain OCT of 107 CH patients - 67 episodic, 35 chronic, five former chronic sufferers - were compared to OCT from 65 healthy individuals. Visual function tests with Sloan charts and a substantial ophthalmologic examination were engaged. RESULTS: Reduction of temporal and temporal-inferior retinal nerve fibre layer (RNFL) thickness was found in both eyes for CH patients with a predominant thinning on the headache side in the temporal-inferior area. Chronic CH patients revealed thinning of the macula compared to episodic suffers and healthy individuals. Bilateral thinning of temporal RNFL was also found in users of 100% oxygen compared to non-users and healthy controls. Visual function did not differ between patients and controls. DISCUSSION: Our OCT findings show a systemic effect causing temporal retinal thinning in both eyes of CH patients possibly due to attack-inherent or medication-induced frequent bilateral vessel diameter changes. The temporal retina with its thinly myelinated parvo-cellular axons and its more susceptible vessels for the vasoconstricting influence of oxygen inhalation seems to be predisposed for tissue damage-causing processes related to CH.

Optic radiation damage in multiple sclerosis is associated with visual dysfunction and retinal thinning--an ultrahigh-field MR pilot study.

OBJECTIVE: To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT). METHODS: We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n = 16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness. RESULTS: Optic radiation lesion volume was associated with thinning of the optic radiation (p < 0.001), delayed VEP (p = 0.031), and visual disability indicated by FACT (p = 0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p < 0.001), including patients without previous optic neuritis (p < 0.001). CONCLUSIONS: Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of acute lesions within the optic radiation in patients with (bilateral) visual disturbances. KEY POINTS: • Focal destruction of the optic radiation is detectable by 7 T MRI. • Focal optic radiation damage is common in MS. • Optic radiation damage is associated with RNFL thinning, detectable by OCT. • Optic radiation damage is associated with delayed VEP and visual dysfunction. • RNFL thickness in non-optic neuritis eyes correlates with optic radiation demyelination.

Metabolic evidence for cerebral neurodegeneration in spinocerebellar ataxia type 1.

Autosomal-dominant spinocerebellar ataxia type 1 (SCA1) is an adult-onset progressive disorder with well-characterized neurodegeneration in the cerebellum and brainstem. The objective of this study is to evaluate neurochemical changes associated with neurodegeneration in cerebral tissue in SCA1 patients compared to age- and gender-matched healthy controls. Nine patients with genetically proven SCA1 and nine gender- and age-matched healthy controls were prospectively recruited from the ataxia clinic and received clinical examination. A 1.5 T single-voxel brain proton MR spectroscopy was performed for total N-acetyl aspartate (tNAA) in cerebellum, parietofrontal lobe white matter, sensory cortex, and visual cortex. In the patients, tNAA was severely decreased in the cerebellar voxel; however, in the voxels positioned in sensory cortex, parietofrontal lobe white matter and visual cortex tNAA was reduced in comparison to controls. In addition to the profoundly affected cerebellum, we also found evidence for cerebral neurodegeneration in parietal lobe white matter, sensory cortex, and visual cortex in SCA1 patients illustrating a multisystem neurodegenerative character of the disease.

Retinal nerve fibre layer thickness correlates with brain white matter damage in multiple sclerosis: a combined optical coherence tomography and diffusion tensor imaging study.

We investigated the association of retinal nerve fibre layer thickness (RNFL) with white matter damage assessed by diffusion tensor imaging (DTI). Forty-four MS patients and 30 healthy subjects underwent optical coherence tomography. DTI was analysed with a voxel-based whole brain and region-based analysis of optic radiation, corpus callosum and further white matter. Correlations between RNFL, fractional anisotropy (FA) and other DTI-based parameters were assessed in patients and controls. RNFL correlated with optic radiation FA, but also with corpus callosum and remaining white matter FA. Our findings demonstrate that RNFL changes indicate white matter damage exceeding the visual pathway.

Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations.

BACKGROUND: Retinal nerve fibre layer (RNFL) thinning is associated with brain atrophy in multiple sclerosis (MS). An influence of optic neuritis is well documented but sparsely investigated. Recently, the retinal ganglion cell layer (GCL) has been shown to provide superior information regarding visual function and retinal neurodegeneration as compared with RNFL. OBJECTIVE: To investigate the association of white and grey matter brain volume with peripapillary RNFL and macular GCL in MS patients with and without a history of optic neuritis. METHODS: 63 patients with relapsing-remitting MS were included in a two-centre cross-sectional prospective study. All patients underwent retinal examination with spectral domain optical coherence tomography and 1.5 T MRI for determination of normalized brain volume (NBV), white matter volume (NWMV) and grey matter volume (NGMV). RESULTS: Both RNFL and GCL were associated with NBV, NWMV and NGMV in eyes without previous optic neuritis. This association is disrupted in the case of NGMV following optic neuritis. CONCLUSIONS: Both RNFL and GCL as parameters of neuro-axonal damage are comparably linked to whole brain as well as white and grey matter atrophy. An event of optic neuritis interferes with this relation, adding further damage to the optic nerve and disrupting especially an association with grey matter.

Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome.

BACKGROUND: Axonal and neuronal damage are widely accepted as key events in the disease course of multiple sclerosis. However, it has been unclear to date at which stage in disease evolution neurodegeneration begins and whether neuronal damage can occur even in the absence of acute inflammatory attacks. OBJECTIVE: To characterize inner retinal layer changes in patients with clinically isolated syndrome (CIS). METHOD: 45 patients with CIS and age- and sex-matched healthy controls were investigated using spectral domain optical coherence tomography. Patients' eyes were stratified into the following categories according to history of optic neuritis (ON): eyes with clinically-diagnosed ON (CIS-ON), eyes with suspected subclinical ON (CIS-SON) as indicated by a visual evoked potential latency of >115 ms and eyes unaffected by ON (CIS-NON). RESULTS: CIS-NON eyes showed significant reduction of ganglion cell- and inner plexiform layer and a topography similar to that of CIS-ON eyes. Seven eyes were characterized as CIS-SON and likewise showed significant retinal layer thinning. The most pronounced thinning was present in CIS-ON eyes. CONCLUSION: Our findings indicate that retinal pathology does occur already in CIS. Intraretinal layer segmentation may be an easily applicable, non-invasive method for early detection of retinal pathology in patients unaffected by ON.

The immune suppressive microenvironment affects efficacy of radio-immunotherapy in brain metastasis.

The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T-cell-directed therapies fail to elicit effective anti-tumor immune responses. Here, we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T-cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastasis. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune suppressive environment to counteract re-activated T-cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune suppression and regulating T-cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

OBJECTIVES: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. METHODS: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). RESULTS: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. INTERPRETATION: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.

Frequent retinal ganglion cell damage after acute optic neuritis.

BACKGROUND: To identify the extent of ganglion cell damage after first-time optic neuritis (ON) using the inter-ocular difference between affected and fellow eyes, and whether this approach is able to detect more patients suffering from ganglion cell damage than using absolute values. METHODS: Thirty-four patients with first-time unilateral ON were followed for a median 413 days. Patients underwent optical coherence tomography testing to determine ganglion cell plus inner plexiform layer thickness (GCIP). Ganglion cell loss was quantified as GCIP difference between ON-affected and fellow eyes (inter-GCIP) and was compared against measurements from 93 healthy controls (HC). Visual function was assessed with high contrast visual acuity; and standard automated perimetry-derived measures of mean deviation and foveal threshold. RESULTS: At clinical presentation after median 19 days from symptom onset, 47.1% of patients showed early GCIP thinning in the ON-affected eye based on inter-GCIP. At the last visit acute ON was associated with 16.1 ±â€¯10.0 µm GCIP thinning compared to fellow eyes (p = 3.669e-06). Based on inter-GCIP, 84.9% of ON patients sustained GCIP thinning in their affected eye at the last visit, whereas using absolute values only 71.0% of patients suffered from GCIP thinning (p = 0.002076). Only 32.3% of these patients had abnormal visual function. The best predictor of GCIP thinning as a measure of ON severity at the last visit was worse visual field mean deviation at clinical presentation. CONCLUSION: Inter-ocular GCIP identifies significantly more eyes suffering damage from ON than absolute GCIP, visual fields or visual acuity loss. Effective interventional options are needed to prevent ganglion cell loss.

Anatomical Wiring and Functional Networking Changes in the Visual System Following Optic Neuritis.

Importance: Clinical outcome in multiple sclerosis was suggested to be driven by not only remyelination but also adaptive reorganization. This mechanism needs to be further understood. Objective: To explore anatomical and functional visual networks in patients with optic neuritis (ON) to assess the relative weight of each connectivity modality to expedite visual recovery. Design, Setting, and Participants: Between March 11, 2011, and May 26, 2014, 39 patients with either clinically isolated syndrome (CIS) ON (n = 18) or other CIS (non-ON) (n = 21) were recruited 1 to 28 months following an initial clinical event. These patients enrolled in an ongoing prospective cohort study (107 participants at the time of this present study) about the disease course of CIS and multiple sclerosis. Inclusion criteria were an age of 18 to 65 years, the suggestive clinical and paraclinical diagnosis of CIS or multiple sclerosis after relevant differential diagnoses have been ruled out, the existence of complete imaging data, and no ocular comorbidities. Anatomical connectivity was evaluated by diffusion tensor imaging, and functional connectivity was evaluated by resting-state functional magnetic resonance imaging. The visual pathways, including optic tracts, optic radiations, and splenial fibers, were delineated, and the resting-state visual networks were detected. Data analysis took place from September 1, 2015, to December 1, 2015. Main Outcomes and Measures: Connectivity changes were quantified and compared to determine the association of ON with the visual network. Results: This study included 18 patients with CIS ON, 11 (61%) of whom were women with a mean (SD) age of 32.83 (8.53) years, and 21 patients with CIS non-ON (11 [52%] of whom were women with a mean [SD] age of 30.86 [7.54] years). With the use of diffusion tensor imaging, reduced diffusivity (mean [SD] fractional anisotropy, 0.35 [0.03] vs 0.38 [0.03]; P < .01) was evident along the optic tracts of patients with ON, suggesting the extension of axonal injury from the damaged optic nerve. Neither the optic radiations nor the splenial fibers showed evidence of loss of integrity. Yet, in the presence of an intact postgeniculate anatomical network, the functional connectivity within the visual network was higher in the ON cohort. Functional connectivity observed in cortical motion-related areas was inversely correlated with the visual evoked potential-measured conduction velocity (r = -0.59; P < .05). Conclusions and Relevance: In this cohort, local optic nerve demyelinating damage does not affect distant wiring, but even in the presence of an intact anatomical network, functional modification may occur. These functional network changes may be part of the recovery process, but further research is needed to elucidate this process.

Multicenter reliability of semiautomatic retinal layer segmentation using OCT.

OBJECTIVE: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans. METHODS: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps. RESULTS: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers. CONCLUSIONS: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.

Association of Retinal Ganglion Cell Layer Thickness With Future Disease Activity in Patients With Clinically Isolated Syndrome.

Importance: Clinically isolated syndrome (CIS) describes a first clinical incident suggestive of multiple sclerosis (MS). Identifying patients with CIS who have a high risk of future disease activity and subsequent MS diagnosis is crucial for patient monitoring and the initiation of disease-modifying therapy. Objective: To investigate the association of retinal optical coherence tomography (OCT) results with future disease activity in patients with CIS. Design, Setting, and Participants: This prospective, longitudinal cohort study took place between January 2011 and May 2017 at 2 German tertiary referral centers. A total of 179 patients with CIS were screened (80 in Berlin and 99 in Munich). Patients underwent neurological examination, magnetic resonance imaging (MRI), and OCT. Only eyes with no previous optic neuritis were considered for OCT analysis. Main Outcomes and Measures: The primary outcome was not meeting the no evidence of disease activity (NEDA-3) criteria; secondary outcomes were MS diagnosis (by the 2010 McDonald criteria) and worsening of disability. The primary measure was OCT-derived ganglion cell and inner plexiform layer thickness; the secondary measures included peripapillary retinal nerve fiber layer thickness, inner nuclear layer thickness, and MRI-derived T2-weighted lesions. Results: A total of 97 of the 179 screened patients (54.2%) were enrolled in the study at a median of 93 (interquartile range [IQR], 62-161) days after a first demyelinating event. The median follow-up duration (Kaplan-Meier survival time) was 729 (IQR, 664-903) days. Of 97 patients with CIS (mean age 33.6 [7.9] years; 61 [62.9%] female), 58 (59%) did not meet NEDA-3 criteria during the follow-up period. A Kaplan-Meier analysis showed a significant probability difference in not meeting NEDA-3 criteria by ganglion cell and inner plexiform later thickness (thinnest vs thickest tertile: hazard ratio [HR], 3.33 [95% CI, 1.70-6.55; P < .001; log-rank P = .001). A follow-up diagnosis of MS was more likely for patients with low ganglion cell and inner plexiform layer thickness (thinnest vs thickest tertile: HR, 4.05 [95% CI, 1.93-8.50]; P < .001). Low peripapillary retinal nerve fiber layer thickness likewise indicated risk of not meeting NEDA-3 criteria (thinnest vs thickest tertile: HR, 2.46 [95% CI, 1.29-4.66]; P = .01; log-rank P = .02). Inner nuclear layer thickness and T2-weighted lesion count were not associated with not meeting NEDA-3 criteria. Conclusions and Relevance: Retinal ganglion cell and inner plexiform layer thickness might prove a valuable imaging marker for anticipating future disease activity and diagnosis of MS in patients with CIS, which can potentially support patient monitoring and initiation of disease-modifying therapy.

Identification of neovascularization by contrast-enhanced ultrasound to detect unstable carotid stenosis.

BACKGROUND: Plaque neovascularization accompanies local inflammation and critically contributes to plaque instability. Correct identification of intraplaque neovascularization by contrast-enhanced ultrasound (CEUS) may provide an additional risk marker in carotid stenosis. This pilot study investigates the correlation between histological evaluation of carotid plaque specimens and pre-surgery CEUS to identify neovascularization. METHODS: 17 patients with high-grade internal carotid artery (ICA) stenosis were studied. CEUS was performed in all patients shortly before carotid endarterectomy. Neovascularization, infiltration of T cells and macrophages along with intraplaque hemorrhage were studied in excised plaques by immunohistochemistry. Ultrasound-based four-level and two-level classification systems for neovascularization were used. CEUS findings were compared with histological findings. RESULTS: Scores on the CEUS-based four-level and two-level classifications were robustly correlated with the density of intraplaque vessels (r = 0.635, p = 0.006 and r = 0.578, p = 0.015, respectively). Histological evaluation of regions with strong and prolonged intraplaque enhancement typically showed strong intraplaque neovascularization in conjunction with acute intraplaque hemorrhage. Moreover, higher grades of intraplaque neovascularization as determined by ultrasound were associated with a higher percentage of macrophage-rich areas. CONCLUSION: CEUS is a technique well suited to gauge the degree of neovascularization of carotid plaques. Future research will have to define the reliability and validity of CEUS in everyday clinical practice. Further, our study suggests that CEUS may also be useful to pick up features of vulnerable plaques such as acute intraplaque hemorrhages.

Pattern of gray matter volumes related to retinal thickness and its association with cognitive function in relapsing-remitting MS.

BACKGROUND: Neurodegeneration in multiple sclerosis (MS) may be investigated in the visual system as optical coherence tomography (OCT) and magnetic resonance imaging (MRI) allows examining structural integrity in detail. The association between thickness of retinal layers and focal cortical volumes beyond the primary visual system has not been thoroughly investigated. OBJECTIVE: To investigate the association between focal cortical volume and thickness of retinal layers. METHODS: Fifty-four patients (relapsing-remitting MS, mean age 40.5 years, mean disease duration 7.6 years, median EDSS 2) underwent OCT and MRI. The association between focal cortical volume and OCT measurements was investigated with voxel-based morphometry (VBM). Patterns of association were determined with Yeo's functional network atlas and the Harvard-Oxford cortical atlas. We used GEE models with cortical volumes from the FreeSurfer parcellation to confirm VBM results. Post hoc, we analyzed the association between OCT, focal cortical volumes, and an extended neuropsychological assessment in a subgroup of 14 patients. RESULTS: Macular retinal nerve fiber layer (mRNFL) and ganglion cell /inner plexiform layer (GCIPL) showed a robust association with mainly the insular cortex and the cingulate cortex. VBM findings were confirmed with FreeSurfer volumes. The post hoc analysis detected significant correlations between both OCT outcomes and cognition. CONCLUSION: Besides the primary visual system, OCT outcomes show a correlation pattern with cortical regions that are known to be important for cognitive performance, predominantly the insula in both hemispheres. Thus, OCT should be further investigated as a marker for neurodegeneration in MS.