Differentiating glaucoma from chiasmal compression using optical coherence tomography: the macular naso-temporal ratio.

BACKGROUND/AIMS: The analysis of visual field loss patterns is clinically useful to guide differential diagnosis of visual pathway pathology. This study investigates whether a novel index of macular atrophy patterns can discriminate between chiasmal compression and glaucoma. METHODS: A retrospective series of patients with preoperative chiasmal compression, primary open-angle glaucoma (POAG) and healthy controls. Macular optical coherence tomography (OCT) images were analysed for the macular ganglion cell and inner plexiform layer (mGCIPL) thickness. The nasal hemi-macula was compared with the temporal hemi-macula to derive the macular naso-temporal ratio (mNTR). Differences between groups and diagnostic accuracy were explored with multivariable linear regression and the area under the receiver operating characteristic curve (AUC). RESULTS: We included 111 individuals (31 with chiasmal compression, 30 with POAG and 50 healthy controls). Compared with healthy controls, the mNTR was significantly greater in POAG cases (ß=0.07, 95% CI 0.03 to 0.11, p=0.001) and lower in chiasmal compression cases (ß=-0.12, 95% CI -0.16 to -0.09, p<0.001), even though overall mGCIPL thickness did not discriminate between these pathologies (p=0.36). The mNTR distinguished POAG from chiasmal compression with an AUC of 95.3% (95% CI 90% to 100%). The AUCs when comparing healthy controls to POAG and chiasmal compression were 79.0% (95% CI 68% to 90%) and 89.0% (95% CI 80% to 98%), respectively. CONCLUSIONS: The mNTR can distinguish between chiasmal compression and POAG with high discrimination. This ratio may provide utility over-and-above previously reported sectoral thinning metrics. Incorporation of mNTR into the output of OCT instruments may aid earlier diagnosis of chiasmal compression.

Associations of Alcohol Consumption and Smoking With Disease Risk and Neurodegeneration in Individuals With Multiple Sclerosis in the United Kingdom.

IMPORTANCE: Understanding the effects of modifiable risk factors on risk for multiple sclerosis (MS) and associated neurodegeneration is important to guide clinical counseling. OBJECTIVE: To investigate associations of alcohol use, smoking, and obesity with odds of MS diagnosis and macular ganglion cell layer and inner plexiform layer (mGCIPL) thickness. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study analyzed data from the community-based UK Biobank study on health behaviors and retinal thickness (measured by optical coherence tomography in both eyes) in individuals aged 40 to 69 years examined from December 1, 2009, to December 31, 2010. Risk factors were identified with multivariable logistic regression analyses. To adjust for intereye correlations, multivariable generalized estimating equations were used to explore associations of alcohol use and smoking with mGCIPL thickness. Finally, interaction models explored whether the correlations of alcohol and smoking with mGCIPL thickness differed for individuals with MS. Data were analyzed from February 1 to July 1, 2021. EXPOSURES: Smoking status (never, previous, or current), alcohol intake (never or special occasions only [low], once per month to ≤4 times per week [moderate], or daily/almost daily [high]), and body mass index. MAIN OUTCOMES AND MEASURES: Multiple sclerosis case status and mGCIPL thickness. RESULTS: A total of 71 981 individuals (38 685 women [53.7%] and 33 296 men [46.3%]; mean [SD] age, 56.7 [8.0] years) were included in the analysis (20 065 healthy control individuals, 51 737 control individuals with comorbidities, and 179 individuals with MS). Modifiable risk factors significantly associated with MS case status were current smoking (odds ratio [OR], 3.05 [95% CI, 1.95-4.64]), moderate alcohol intake (OR, 0.62 [95% CI, 0.43-0.91]), and obesity (OR, 1.72 [95% CI, 1.15-2.56]) compared with healthy control individuals. Compared with the control individuals with comorbidities, only smoking was associated with case status (OR, 2.30 [95% CI, 1.48-3.51]). High alcohol intake was associated with a thinner mGCIPL in individuals with MS (adjusted ß = -3.09 [95% CI, -5.70 to -0.48] µm; P = .02). In the alcohol interaction model, high alcohol intake was associated with thinner mGCIPL in control individuals (ß = -0.93 [95% CI, -1.07 to -0.79] µm; P < .001), but there was no statistically significant association in individuals with MS (ß = -2.27 [95% CI, -4.76 to 0.22] µm; P = .07). Smoking was not associated with mGCIPL thickness in MS. However, smoking was associated with greater mGCIPL thickness in control individuals (ß = 0.89 [95% CI, 0.74-1.05 µm]; P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that high alcohol intake was associated with retinal features indicative of more severe neurodegeneration, whereas smoking was associated with higher odds of being diagnosed with MS.

Optical Coherence Tomography Angiography (OCTA) in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder.

Vascular changes are increasingly recognized as important factors in the pathophysiology of neuroinflammatory disease, especially in multiple sclerosis (MS). The relatively novel technology of optical coherence tomography angiography (OCTA) images the retinal and choroidal vasculature non-invasively and in a depth-resolved manner. OCTA provides an alternative quantitative measure of retinal damage, by measuring vascular density instead of structural atrophy. Preliminary results suggest OCTA is sensitive to retinal damage in early disease stages, while also having less of a "floor-effect" compared with commonly used OCT metrics, meaning it can pick up further damage in a severely atrophied retina in later stages of disease. Furthermore, it may serve as a surrogate marker for vascular pathology in the central nervous system. Data to date consistently reveal lower densities of the retinal microvasculature in both MS and neuromyelitis optica spectrum disorder (NMOSD) compared with healthy controls, even in the absence of prior optic neuritis. Exploring the timing of vascular changes relative to structural atrophy may help answer important questions about the role of hypoperfusion in the pathophysiology of neuroinflammatory disease. Finally, qualitative characteristics of retinal microvasculature may help discriminate between different neuroinflammatory disorders. There are however still issues regarding image quality and development of standardized analysis methods before OCTA can be fully incorporated into clinical practice.

Acute anosmia in neuromyelitis optica spectrum disorder.

The cardinal features of neuromyelitis optica spectrum disorder (NMOSD) are optic neuritis, longitudinal extensive transverse myelitis and area postrema syndrome. Olfactory dysfunction is not listed as a feature in the NMOSD diagnostic criteria. Here, we present an aquaporin-4 antibody positive patient who, in addition to classical features of NMOSD, developed acute anosmia with magnetic resonance imaging (MRI) evidence of olfactory bulb abnormalities. While the association of anosmia and NMOSD has been rarely noted previously, to our knowledge, no prior cases have found this to be one of the presenting features of a relapse nor have they identified acute radiological correlates.

CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD.

OBJECTIVE: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis. METHODS: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37). RESULTS: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased. CONCLUSIONS: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.

Anterior visual system imaging to investigate energy failure in multiple sclerosis.

Mitochondrial failure and hypoxia are key contributors to multiple sclerosis pathophysiology. Importantly, improving mitochondrial function holds promise as a new therapeutic strategy in multiple sclerosis. Currently, studying mitochondrial changes in multiple sclerosis is hampered by a paucity of non-invasive techniques to investigate mitochondrial function of the CNS in vivo. It is against this backdrop that the anterior visual system provides new avenues for monitoring of mitochondrial changes. The retina and optic nerve are among the metabolically most active structures in the human body and are almost always affected to some degree in multiple sclerosis. Here, we provide an update on emerging technologies that have the potential to indirectly monitor changes of metabolism and mitochondrial function. We report on the promising work with optical coherence tomography, showing structural changes in outer retinal mitochondrial signal bands, and with optical coherence angiography, quantifying retinal perfusion at the microcapillary level. We show that adaptive optics scanning laser ophthalmoscopy can visualize live perfusion through microcapillaries and structural changes at the level of single photoreceptors and neurons. Advantages and limitations of these techniques are summarized with regard to future research into the pathology of the disease and as trial outcome measures.

Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis.

Importance: The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. Objective: To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. Design, Setting and Participants: This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. Main Outcomes and Measures: Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. Results: Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman ρ, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms. Conclusions and Relevance: Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance.

Disease activity following pregnancy-related discontinuation of natalizumab in MS.

OBJECTIVE: To investigate disease activity and disability progression following pregnancy-related discontinuation of natalizumab (NTZ) in patients with relapsing-remitting MS. METHODS: A retrospective cohort study of clinical and radiologic data in patients who discontinued NTZ for pregnancy-related reasons. RESULTS: Twenty-two pregnancy-related NTZ discontinuations in 17 patients were evaluated. The median time to conception was 3.4 months. Relapses were more frequent in patients in whom conception did not occur within 6 months (p = 0.022). Confirmed disability progression occurred in 27.3% and was associated with time to conception (p < 0.001). CONCLUSIONS: Early conception after NTZ discontinuation is associated with a reduced risk of disease activity and disability progression. Continuation of NTZ treatment until confirmed pregnancy should be considered in patients with previously active MS. However, the advantages of continuing the drug until pregnancy should be balanced against the uncertainties in postnatal outcomes.

The effect of aging on fronto-striatal reactive and proactive inhibitory control.

Inhibitory control, like most cognitive processes, is subject to an age-related decline. The effect of age on neurofunctional inhibition processing remains uncertain, with age-related increases as well as decreases in activation being reported. This is possibly because reactive (i.e., outright stopping) and proactive inhibition (i.e., anticipation of stopping) have not been evaluated separately. Here, we investigate the effects of aging on reactive as well as proactive inhibition, using functional MRI in 73 healthy subjects aged 30-70years. We found reactive inhibition to slow down with advancing age, which was paralleled by increased activation in the motor cortex. Behaviorally, older adults did not exercise increased proactive inhibition strategies compared to younger adults. However, the pattern of activation in the right inferior frontal gyrus (rIFG) showed a clear age-effect on proactive inhibition: rather than flexibly engaging the rIFG in response to varying stop-signal probabilities, older subjects showed an overall hyperactivation. Whole-brain analyses revealed similar hyperactivations in various other frontal and parietal brain regions. These results are in line with the neural compensation hypothesis of aging: processing becomes less flexible and efficient with advancing age, which is compensated for by overall enhanced activation. Moreover, by disentangling reactive and proactive inhibition, we can show for the first time that the age-related increase in activation during inhibition that is reported generally by prior studies may be the result of compensation for reduced neural flexibility related to proactive control strategies.

Impact of aging on frontostriatal reward processing.

Healthy aging is associated with a progressive decline across a range of cognitive functions. An important factor underlying this decline may be the age-related impairment in stimulus-reward processing. Several studies have investigated age-related effects, but compared young versus old subjects. This is the first study to investigate the effect of aging on brain activation during reward processing within a continuous segment of the adult life span. We scanned 49 healthy adults aged 40-70 years, using functional MRI. We adopted a simple reward task, which allowed separate evaluation of neural responses to reward anticipation and receipt. The effect of reward on performance accuracy and speed was not related to age, indicating that all subjects could perform the task correctly. We identified a whole-brain significant age-related decline of ventral striatum activation during reward anticipation as compared to neutral anticipation. Importantly, the specificity of this finding was underscored by the observation that there was no general decline in activation during anticipation. Activation in the ventral striatum increased with age during reward receipt as compared to receiving neutral outcome. Finally, activation in the ventromedial prefrontal cortex during outcome was not affected by age. Our data demonstrate that the typical shift in striatal activation from reward receipt to reward anticipation in young adults disappears with healthy aging. These changes are consistent the well-ocumented age-related decline of striatal dopamine availability, and may provide a stepping stone for further research of age-related neurodegenerative diseases.

Grayanotoxin poisoning: 'mad honey disease' and beyond.

Many plants of the Ericaceae family, Rhododendron, Pieris, Agarista and Kalmia, contain diterpene grayanotoxins. Consumption of grayanotoxin containing leaves, flowers or secondary products as honey may result in intoxication specifically characterized by dizziness, hypotension and atrial-ventricular block. Symptoms are caused by an inability to inactivate neural sodium ion channels resulting in continuous increased vagal tone. Grayanotoxin containing products are currently sold online, which may pose an increasing risk. In humans, intoxication is rarely lethal, in contrast to cattle and pet poisoning cases. Scientific evidence for the medicinal properties of grayanotoxin containing preparations, such as honey or herbal preparation in use in folk medicine, is scarce, and such use may even be harmful.