Ocular Findings of Cryptococcal Meningitis in Previously Healthy Adults.

BACKGROUND: Patients with cryptococcal meningitis (CM) often have ocular manifestations; although data are describing these findings in nonimmunosuppressed, previously healthy individuals are scarce. METHODS: A retrospective chart review was performed for previously healthy patients with CM who underwent a complete ophthalmological examination within a 5-year period at the National Institutes of Health. Demographics, CSF parameters, findings on initial ophthalmological examination, and MRI abnormalities were analyzed. RESULTS: Forty-four patients within a median of 12 weeks after CM diagnosis were included in our study; 27 patients (61%) reported abnormal vision on presentation. Seventy-one percent of patients were not shunted at the time of their initial eye examination. The most common ocular abnormalities were visual field defects in 21 (66%), decreased visual acuity in 14 (38%), and papilledema in 8 (26%) patients. Intraocular pressure was within normal range in all patients. Cranial nerve defects were identified in 5 patients and optic neuropathy in 2 patients. Patients who had hydrocephalus or did not receive a ventriculoperitoneal shunt were not noted to have worse ocular abnormalities. CONCLUSIONS: The most common ocular findings in our cohort of nontransplant, non-HIV cryptococcal meningitis patients were visual field defects, decreased visual acuity, and papilledema. Our results emphasize the need for a comprehensive eye examination in patients with CM who may not always report a change in vision on presentation.

Manipulating the Fourier spectra of stimuli comprising a two-frame kinematogram to study early visual motion-detecting mechanisms: Perception versus short latency ocular-following responses.

Two-frame kinematograms have been extensively used to study motion perception in human vision. Measurements of the direction-discrimination performance limits (Dmax) have been the primary subject of such studies, whereas surprisingly little research has asked how the variability in the spatial frequency content of individual frames affects motion processing. Here, we used two-frame one-dimensional vertical pink noise kinematograms, in which images in both frames were bandpass filtered, with the central spatial frequency of the filter manipulated independently for each image. To avoid spatial aliasing, there was no actual leftward-rightward shift of the image: instead, the phases of all Fourier components of the second image were shifted by ±» wavelength with respect to those of the first. We recorded ocular-following responses (OFRs) and perceptual direction discrimination in human subjects. OFRs were in the direction of the Fourier components' shift and showed a smooth decline in amplitude, well fit by Gaussian functions, as the difference between the central spatial frequencies of the first and second images increased. In sharp contrast, 100% correct perceptual direction-discrimination performance was observed when the difference between the central spatial frequencies of the first and second images was small, deteriorating rapidly to chance when increased further. Perceptual dependencies moved closer to the OFR ones when subjects were allowed to grade the strength of perceived motion. Response asymmetries common for perceptual judgments and the OFRs suggest that they rely on the same early visual processing mechanisms. The OFR data were quantitatively well described by a model which combined two factors: (1) an excitatory drive determined by a power law sum of stimulus Fourier components' contributions, scaled by (2) a contrast normalization mechanism. Thus, in addition to traditional studies relying on perceptual reports, the OFRs represent a valuable behavioral tool for studying early motion processing on a fine scale.

Weighted summation and contrast normalization account for short-latency disparity vergence responses to white noise stimuli in humans.

Natural images are typically broadband, whereas detectors in early visual processing are selective for narrow ranges of spatial frequency. White noise patterns are widely used in laboratory settings to investigate how responses are derived from Fourier components in the image. Here, we report disparity vergence responses (DVRs) to white noise stimuli in human subjects and compare these with responses to white noise patterns filtered with bandpass filters and notch filters and to sinusoidal gratings. Although the contribution of these short-latency eye movements to the overall vergence response to a given stimulus is generally small, they have proven to be a valuable tool for the study of the early mechanisms that process disparity stimuli in human subjects. Removing lower spatial frequency (SF) components reduced DVR amplitude, whereas removing higher SF components led to an increase in DVR amplitude. For larger disparities, the transition occurred at lower SFs. All of these effects were quantitatively well described by a model that combined two factors: (a) an excitatory drive determined by a weighted sum of stimulus Fourier components, which was scaled by (b) a contrast normalization mechanism.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Short-latency ocular following responses to motion stimuli are strongly affected by temporal modulations of the visual content during the initial fixation period.

Neuronal and psychophysical responses to a visual stimulus are known to depend on the preceding history of visual stimulation, but the effect of stimulation history on reflexive eye movements has received less attention. Here, we quantify these effects using short-latency ocular following responses (OFRs), a valuable tool for studying early motion processing. We recorded, in human subjects, the horizontal OFRs induced by drifting vertical 1D pink noise. The stimulus was preceded by 600 to 1000 ms of maintained fixation (on a visible cross), and we explored the effect of different stimuli ("fixation patterns") presented during the fixation period. We found that any temporal modulation present during the fixation period reduced the magnitude of the subsequent OFRs. Even changes in the overall luminance during the fixation period induced significant suppression. The magnitude of the effect was a function of both spatial and temporal structure of the fixation pattern. Suppression that was selective for both relative orientation and relative spatial frequency accounted for a considerable fraction of total suppression. Finally, changes in stimulus temporal structure alone (i.e. "flicker" versus "transparent motion") led to changes in the spatial frequency tuning of suppression. In the time domain, the suppression developed quickly: 100 ms of temporal modulation in the fixation pattern produced up to 80% of maximal suppression. Recovery from suppression was instead more gradual, taking up to several seconds. By presenting transparent motion during the fixation period, with opposite motion signals having different spatial frequency content, we also discovered a direction-selective component of suppression, which depended on both the frequency and the direction of the moving stimulus.

Successful Intravascular Treatment of an Intraosseous Arteriovenous Fistula in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a benign bone disease characterized by expansile lesions that typically stabilize with age. Rarely, FD can undergo malignant transformation, presenting with atypical, rapid growth and destruction of adjacent bone. Other potential causes of rapid FD expansion include secondary lesions, such as aneurysmal bone cysts. We describe a case of an aggressive occipital lesion that presented with pain associated with diplopia and tinnitus, raising concern for malignant transformation. A massive intraosseous arteriovenous fistula was identified giving rise to an anomalous vein coursing to the cavernous sinus with compression of the abducens nerve. The vascular anomaly was mapped and after embolization symptoms resolved; a biopsy with extensive genetic analyses excluded malignancy. The differential diagnosis for expanding FD lesions includes aggressive FD, malignant transformation, and secondary vascular anomalies. In cases when traditional radiographic and histologic assessments are nondescript, use of additional radiographic modalities and genetic analyses are required to make an accurate diagnosis and guide treatment. When vascular anomalies are suspected, detailed angiography with embolization is necessary to define and treat the lesion. However, to rule out malignant transformation, genetic screening is recommended.

Short-latency ocular-following responses: Weighted nonlinear summation predicts the outcome of a competition between two sine wave gratings moving in opposite directions.

We recorded horizontal ocular-following responses to pairs of superimposed vertical sine wave gratings moving in opposite directions in human subjects. This configuration elicits a nonlinear interaction: when the relative contrast of the gratings is changed, the response transitions abruptly between the responses elicited by either grating alone. We explore this interaction in pairs of gratings that differ in spatial and temporal frequency and show that all cases can be described as a weighted sum of the responses to each grating presented alone, where the weights are a nonlinear function of stimulus contrast: a nonlinear weighed summation model. The weights depended on the spatial and temporal frequency of the component grating. In many cases the dominant component was not the one that produced the strongest response when presented alone, implying that the neuronal circuits assigning weights precede the stages at which motor responses to visual motion are generated. When the stimulus area was reduced, the relationship between spatial frequency and weight shifted to higher frequencies. This finding may reflect a contribution from surround suppression. The nonlinear interaction is strongest when the two components have similar spatial frequencies, suggesting that the nonlinearity may reflect interactions within single spatial frequency channels. This framework can be extended to stimuli composed of more than two components: our model was able to predict the responses to stimuli composed of three gratings. That this relatively simple model successfully captures the ocular-following responses over a wide range of spatial/temporal frequency and contrast parameters suggests that these interactions reflect a simple mechanism.

Evidence From Parkinson's Disease That the Superior Colliculus Couples Action and Perception.

BACKGROUND: Action and perception should be coordinated for good visual-motor performance. The mechanism coupling action and perception may be a prominence map in the intermediate layer of the superior colliculus that modulates motor and attentional/perceptual processes. This coordination comes with a cost: the misperception that briefly overlapping stimuli are separated in time. Our model predicts that abnormal intermediate layer of the superior colliculus inhibition, such as that arising from increased basal ganglia output, would affect the action and perception coupling, and it would worsen the misperception. OBJECTIVE: To test the prominence map model by measuring reaction times and perceptions in human intermediate layer of the superior colliculus dysfunction. METHODS: We measured the saccadic and perceptual reaction time changes and the percept for different temporal asynchronies between fixation point offset and peripheral target onset in Parkinson's disease (PD). RESULTS: We found that increased basal ganglia inhibitory output to the intermediate layer of the superior colliculus prominence map disrupted the normal coupling of action and perception. With increasing temporal asynchronies, the PD perceptual reaction times increased approximately 3 times more than the increase of the saccadic reaction times. Also, PD subjects misperceive small overlaps as gaps for temporal asynchronies up to 3 times longer than controls. The results can be reproduced by an intermediate layer of the superior colliculus rostral-caudal gradient of inhibition. CONCLUSION: These findings support the hypothesis that a prominence map in the intermediate layer of the superior colliculus couples action and perception through modulation of attention. A dysfunction of this network quantifies abnormal basal ganglia output and could underlie visual deficits, including common, yet poorly understood, misperceptions and visual-motor deficits of PD. © 2019 International Parkinson and Movement Disorder Society.

Action and perception are temporally coupled by a common mechanism that leads to a timing misperception.

We move our eyes to explore the world, but visual areas determining where to look next (action) are different from those determining what we are seeing (perception). Whether, or how, action and perception are temporally coordinated is not known. The preparation time course of an action (e.g., a saccade) has been widely studied with the gap/overlap paradigm with temporal asynchronies (TA) between peripheral target onset and fixation point offset (gap, synchronous, or overlap). However, whether the subjects perceive the gap or overlap, and when they perceive it, has not been studied. We adapted the gap/overlap paradigm to study the temporal coupling of action and perception. Human subjects made saccades to targets with different TAs with respect to fixation point offset and reported whether they perceived the stimuli as separated by a gap or overlapped in time. Both saccadic and perceptual report reaction times changed in the same way as a function of TA. The TA dependencies of the time change for action and perception were very similar, suggesting a common neural substrate. Unexpectedly, in the perceptual task, subjects misperceived lights overlapping by less than ∼100 ms as separated in time (overlap seen as gap). We present an attention-perception model with a map of prominence in the superior colliculus that modulates the stimulus signal's effectiveness in the action and perception pathways. This common source of modulation determines how competition between stimuli is resolved, causes the TA dependence of action and perception to be the same, and causes the misperception.

Ocular-following responses to white noise stimuli in humans reveal a novel nonlinearity that results from temporal sampling.

White noise stimuli are frequently used to study the visual processing of broadband images in the laboratory. A common goal is to describe how responses are derived from Fourier components in the image. We investigated this issue by recording the ocular-following responses (OFRs) to white noise stimuli in human subjects. For a given speed we compared OFRs to unfiltered white noise with those to noise filtered with band-pass filters and notch filters. Removing components with low spatial frequency (SF) reduced OFR magnitudes, and the SF associated with the greatest reduction matched the SF that produced the maximal response when presented alone. This reduction declined rapidly with SF, compatible with a winner-take-all operation. Removing higher SF components increased OFR magnitudes. For higher speeds this effect became larger and propagated toward lower SFs. All of these effects were quantitatively well described by a model that combined two factors: (a) an excitatory drive that reflected the OFRs to individual Fourier components and (b) a suppression by higher SF channels where the temporal sampling of the display led to flicker. This nonlinear interaction has an important practical implication: Even with high refresh rates (150 Hz), the temporal sampling introduced by visual displays has a significant impact on visual processing. For instance, we show that this distorts speed tuning curves, shifting the peak to lower speeds. Careful attention to spectral content, in the light of this nonlinearity, is necessary to minimize the resulting artifact when using white noise patterns undergoing apparent motion.

Corollary discharge contributes to perceived eye location in monkeys.

Despite saccades changing the image on the retina several times per second, we still perceive a stable visual world. A possible mechanism underlying this stability is that an internal retinotopic map is updated with each saccade, with the location of objects being compared before and after the saccade. Psychophysical experiments have shown that humans derive such location information from a corollary discharge (CD) accompanying saccades. Such a CD has been identified in the monkey brain in a circuit extending from superior colliculus to frontal cortex. There is a missing piece, however. Perceptual localization is established only in humans and the CD circuit only in monkeys. We therefore extended measurement of perceptual localization to the monkey by adapting the target displacement detection task developed in humans. During saccades to targets, the target disappeared and then reappeared, sometimes at a different location. The monkeys reported the displacement direction. Detections of displacement were similar in monkeys and humans, but enhanced detection of displacement from blanking the target at the end of the saccade was observed only in humans, not in monkeys. Saccade amplitude varied across trials, but the monkey's estimates of target location did not follow that variation, indicating that eye location depended on an internal CD rather than external visual information. We conclude that monkeys use a CD to determine their new eye location after each saccade, just as humans do.

Ocular following in humans: spatial properties.

Ocular following responses (OFRs) are tracking eye movements elicited at ultrashort latency by the sudden movement of a textured pattern. Here we report the results of our study of their dependency on the spatial arrangement of the motion stimulus. Unlike previous studies that looked at the effect of stimulus size, we investigated the impact of stimulus location and how two distinct stimuli, presented together, collectively determine the OFR. We used as stimuli vertical gratings that moved in the horizontal direction and that were confined to either one or two 0.58° high strips, spanning the width of the screen. We found that the response to individual strips varied as a function of the location and spatial frequency (SF) of the stimulus. The response decreased as the stimulus eccentricity increased, but this relationship was more accentuated at high than at low spatial frequencies. We also found that when pairs of stimuli were presented, nearby stimuli interacted strongly, so that the response to the pair was barely larger than the response to a single strip in the pair. This suppressive effect faded away as the separation between the strips increased. The variation of the suppressive interaction with strip separation, paired with the dependency on eccentricity of the responses to single strips, caused the peak response for strip pairs to be achieved at a specific separation, which varied as a function of SF.

Optic disc Edema in patients with fibrous dysplasia/McCune-Albright syndrome: Craniomorphometric analysis and peripapillary retinal nerve fiber layer data.

This article reports quantitative measurements of intracranial volume, optic canal area, and peripapillary retinal nerve fiber layer (RNFL) for a cohort of 124 patients with craniofacial fibrous dysplasia/McCune-Albright Syndrome (FD/MAS), previously used to determine risks for developing optic disc edema [1]. Of these, 7 subjects were diagnosed with optic disc edema. OSIRIX imaging analysis software was used to collect intracranial volume and optic canal diameter for 107 patients, via 3D multiplanar reconstruction (MPR) of ≤5 mm axial CT slices. Spectral-domain Optical Coherence Tomography (OCT) was performed with the Cirrus-HD OCT (Carl Zeiss Meditec, Inc., Dublin, CA). The Optic Disc Cube 200 × 200 protocol was used for acquisition and analysis of the RNFL for 69 patients. The data can be used to assess typical ranges for intracranial volume, optic canal area, and RNFL in the craniofacial FD/MAS population and to assess ranges concerning for optic disc edema. [1] Raborn LN, Pan KS, FitzGibbon EJ, Collins MT, Boyce AM. Optic disc edema in fibrous dysplasia/McCune-Albright syndrome: Prevalence, etiologies, and clinical implications. Bone. 2021 Feb;143:115661. doi: 10.1016/j.bone.2020.115661. Epub 2020 Sep 24. PMID: 32979536.

Optic disc edema in fibrous dysplasia/McCune-Albright syndrome: Prevalence, etiologies, and clinical implications.

BACKGROUND: Fibrous dysplasia (FD) is a rare disorder of expansile fibro-osseous lesions that may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). Optic disc edema is a potentially serious ophthalmologic finding that has been rarely reported in patients with FD/MAS. The purpose of this study was to investigate the prevalence and potential clinical associations of optic disc edema in a large cohort. METHODS: Clinical records were reviewed from subjects in an ongoing FD/MAS natural history study. Computed Tomography scans were evaluated for the presence of structural craniofacial abnormalities associated with optic disc edema, including Chiari I malformation and space-occupying lesions. Craniomorphometric analyses were performed to determine optic canal diameter and intracranial volume. Statistical analyses were performed to compare clinical and radiographic features between subjects with and without optic disc edema. RESULTS: Optic disc edema was diagnosed in 7/187 subjects, for a prevalence of 3.7%. All subjects with optic disc edema were diagnosed before age 18 years and had mild, non-progressive disease. Radiographic structural abnormalities, including Chiari I malformation, aneurysmal bone cysts, and arachnoid cysts, were associated with higher odds of optic disc edema (odds ratio [OR] 24.3; 95% confidence interval [CI], 4.2 to 121.4; p < 0.01) (OR 18.0; 95% CI, 3.4 to 108.2; p < 0.01). Treatment with leuprolide, a gonadotropin releasing hormone analog, was also associated with optic disc edema (OR 26.0; 95% CI 3.3 to 177.5; p < 0.05). There was no significant association of optic disc edema with other MAS endocrinopathies, medications, optic canal diameter, or intracranial volume. CONCLUSION: Optic disc edema is an uncommon but potentially serious complication of craniofacial FD, which may occur more frequently in pediatric patients and those with structural craniofacial abnormalities. The potential association of leuprolide therapy with optic disc edema in this population warrants further study.

A sialidosis type I cohort and a quantitative approach to multimodal ophthalmic imaging of the macular cherry-red spot.

AIM: To describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated 'macular cherry-red spot'. METHODS: Seven patients with sialidosis type I (mutations in NEU1) and one with galactosialidosis (mutations in CTSA) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years. RESULTS: The mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50)+0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to age-matched controls (p<0.0001). CONCLUSION: Most of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear. TRIAL REGISTRATION NUMBER: NCT00029965.

Amplitudes and directions of individual saccades can be adjusted by corollary discharge.

There is strong evidence that the brain can use an internally generated copy of motor commands, a corollary discharge, to guide rapid sequential saccades. Much of this evidence comes from the double-step paradigm: after two briefly flashed visual targets have disappeared, the subject makes two sequential saccades to the targets. Recent studies on the monkey revealed that amplitude variations of the first saccade led to compensation by the second saccade, mediated by a corollary discharge. Here, we investigated whether such saccade-by-saccade compensation occurs in humans, and we made three new observations. First, we replicated previous findings from the monkey: following first saccade amplitude variations, the direction of the second saccade compensated for the error. Second, the change in direction of the second saccade followed variations in vertical as well as horizontal first saccades although the compensation following horizontal saccades was significantly more accurate. Third, by examining oblique saccades, we are able to show that first saccade variations are compensated by adjustment in saccade amplitude in addition to direction. Together, our results demonstrate that it is likely that a corollary discharge in humans can be used to adjust both saccade direction and amplitude following variations in individual saccades.

Eye movement sequence generation in humans: Motor or goal updating?

Saccadic eye movements are often grouped in pre-programmed sequences. The mechanism underlying the generation of each saccade in a sequence is currently poorly understood. Broadly speaking, two alternative schemes are possible: first, after each saccade the retinotopic location of the next target could be estimated, and an appropriate saccade could be generated. We call this the goal updating hypothesis. Alternatively, multiple motor plans could be pre-computed, and they could then be updated after each movement. We call this the motor updating hypothesis. We used McLaughlin's intra-saccadic step paradigm to artificially create a condition under which these two hypotheses make discriminable predictions. We found that in human subjects, when sequences of two saccades are planned, the motor updating hypothesis predicts the landing position of the second saccade in two-saccade sequences much better than the goal updating hypothesis. This finding suggests that the human saccadic system is capable of executing sequences of saccades to multiple targets by planning multiple motor commands, which are then updated by serial subtraction of ongoing motor output.

Absent optic chiasm presenting with horizontal nystagmus.

A female infant with horizontal nystagmus and normal ophthalmic examination had isolated absence of the optic chiasm on magnetic resonance imaging. Eye movements were recorded on video and reviewed. Horizontal nystagmus without see-saw nystagmus was observed. Visual evoked potential showed inter-hemispheric asymmetry compatible with the absence of crossing chiasmal fibers. Systemic abnormalities in this patient included cleft lip, preauricular skin tags, broad thumbs, and an anteriorly positioned anus, suggestive of Townes-Brock syndrome.

Utility of Optical Coherence Tomography in the Diagnosis and Management of Optic Neuropathy in Patients with Fibrous Dysplasia.

Optic neuropathy (ON) is a highly disabling complication of fibrous dysplasia (FD). The optimal test for identifying and monitoring ON in FD is unknown. Optical coherence tomography (OCT) is an imaging modality that detects retinal nerve fiber layer (RNFL) thinning, a sign of optic nerve atrophy. The purpose of this study was to (i) assess the ability of OCT RNFL thickness measurements to identify ON in FD; (ii) compare the performance of RNFL thickness to computed tomography measurements; and (iii) examine changes in RNFL thickness over time to assess disease progression. A retrospective cohort study was performed to assess subjects (n = 70) who underwent neuro-ophthalmologic examination, including OCT. The diagnostic utility of RNFL thickness was determined using receiver operator characteristic (ROC) curve analysis, and the accuracy was compared with computed tomography measurements. The relationship between RNFL thickness and age was assessed cross-sectionally, using generalized estimating equation methodology, and longitudinally, using a generalized mixed model. Eleven subjects were identified with ON. RNFL thickness identified ON (area under curve = 0.997, p < 0.0001) with sensitivity and specificity of 100% and 95%, respectively, when using the diagnostic criterion of ≤71 µm. RNFL thickness outperformed computed tomography measurements of optic canal narrowing and optic nerve stretch. Subjects with ON exhibited a greater decrease in RNFL thickness with each year of age (-0.70 µm/year, p < 0.001) than subjects with normal vision (-0.16 µm/year, p < 0.05). When assessed longitudinally, subjects with normal vision demonstrated an increase in RNFL thickness until approximately age 20 years that decreased thereafter. In contrast, subjects with ON exhibited an earlier decrease in RNFL thickness during adolescence. In conclusion, RNFL thickness of ≤71 µm accurately identified ON in this population. By establishing the difference in rate of RNFL thinning in patients with and without ON, clinicians may distinguish between patients at risk for ON and intervene before irreversible damage. © 2020 American Society for Bone and Mineral Research.

Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry.

In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome (n = 21), other congenital facial weakness disorders (n = 9) and healthy controls (n = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this 'landmark' region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.