Neurology and the histiocytoses: a case of Rosai-Dorfman-Destombes disease.

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease. We present a challenging diagnostic and management case of Rosai-Dorfman-Destombes disease in a 48-year-old woman with a relapsing, partially steroid-responsive syndrome comprising patchy, non-length-dependent radiculoneuropathy with diffuse pachymeningitis and widespread systemic disease, and recent dramatic response to novel mitogen-activated kinase pathway inhibition. We discuss the clinical characteristics, diagnosis, recent breakthroughs in pathogenesis and emerging treatment options for Rosai-Dorfman disease and for the histiocytoses with neurological sequelae, including Langerhans cell histiocytosis and Erdheim-Chester disease.

Evidence That Pupil Size and Reactivity Are Determined More by Your Parents Than by Your Environment.

Purpose: A classic twin study to evaluate the relative contributions of genetic and environmental factors to resting pupil size and reactivity. Methods: Pupillometry was performed on 326 female twins (mean age 64 years) from the TwinsUK Adult Twin Registry, assessing resting pupil diameter in darkness and increasing levels of ambient light, alongside dynamic pupillary characteristics. Maximum-likelihood structural equation models estimated the proportion of trait variance attributable to genetic factors. Results: Mean (SD) pupil diameter in darkness was 5.29 mm (0.81), decreasing to 3.24 mm (0.57) in bright light. Pupil light reaction (PLR) had a mean (SD) amplitude of 1.38 mm (0.27) and latency of 250.34 milliseconds (28.58). Pupil size and PLR were not associated with iris colour, intraocular pressure or refractive error, but were associated with age (diameter ß = -0.02, p = 0.016, constriction amplitude ß = -0.01, p < 0.001, velocity ß = 0.03, p < 0.001, and latency ß = 0.98, p < 0.001). In darkness the resting pupil size showed a MZ intraclass correlation coefficient of 0.85, almost double that of DZ (0.44), suggesting strong additive genetic effects, with the most parsimonious model estimating a heritability of 86% [95% confidence interval (CI) 79-90%] with 14% (95% CI 10-21%) explained by unique environmental factors. PLR amplitude, latency and constriction velocity had estimated heritabilities of 69% (95% CI 54-79%), 40% (95% CI 21-56%), and 64% (95% CI 48-75%), respectively. Conclusion: Genetic effects are key determinants of resting pupil size and reactivity. Future studies to identify these genetic factors could improve our understanding of variation in pupil size and pupillary reactions in health and disease.

Sequence of clinical and neurodegeneration events in Parkinson's disease progression.

Dementia is one of the most debilitating aspects of Parkinson's disease. There are no validated biomarkers that can track Parkinson's disease progression, nor accurately identify patients who will develop dementia and when. Understanding the sequence of observable changes in Parkinson's disease in people at elevated risk for developing dementia could provide an integrated biomarker for identifying and managing individuals who will develop Parkinson's dementia. We aimed to estimate the sequence of clinical and neurodegeneration events, and variability in this sequence, using data-driven statistical modelling in two separate Parkinson's cohorts, focusing on patients at elevated risk for dementia due to their age at symptom onset. We updated a novel version of an event-based model that has only recently been extended to cope naturally with clinical data, enabling its application in Parkinson's disease for the first time. The observational cohorts included healthy control subjects and patients with Parkinson's disease, of whom those diagnosed at age 65 or older were classified as having high risk of dementia. The model estimates that Parkinson's progression in patients at elevated risk for dementia starts with classic prodromal features of Parkinson's disease (olfaction, sleep), followed by early deficits in visual cognition and increased brain iron content, followed later by a less certain ordering of neurodegeneration in the substantia nigra and cortex, neuropsychological cognitive deficits, retinal thinning in dopamine layers, and further deficits in visual cognition. Importantly, we also characterize variation in the sequence. We found consistent, cross-validated results within cohorts, and agreement between cohorts on the subset of features available in both cohorts. Our sequencing results add powerful support to the increasing body of evidence suggesting that visual processing specifically is affected early in patients with Parkinson's disease at elevated risk of dementia. This opens a route to earlier and more precise detection, as well as a more detailed understanding of the pathological mechanisms underpinning Parkinson's dementia.

Visual tests predict dementia risk in Parkinson disease.

OBJECTIVE: To assess the role of visual measures and retinal volume to predict the risk of Parkinson disease (PD) dementia. METHODS: In this cohort study, we collected visual, cognitive, and motor data in people with PD. Participants underwent ophthalmic examination, retinal imaging using optical coherence tomography, and visual assessment including acuity and contrast sensitivity and high-level visuoperception measures of skew tolerance and biological motion. We assessed the risk of PD dementia using a recently described algorithm that combines age at onset, sex, depression, motor scores, and baseline cognition. RESULTS: One hundred forty-six people were included in the study (112 with PD and 34 age-matched controls). The mean disease duration was 4.1 (±2·5) years. None of these participants had dementia. Higher risk of dementia was associated with poorer performance in visual measures (acuity: ρ = 0.29, p = 0.0024; contrast sensitivity: ρ = -0.37, p < 0.0001; skew tolerance: ρ = -0.25, p = 0.0073; and biological motion: ρ = -0.26, p = 0.0054). In addition, higher risk of PD dementia was associated with thinner retinal structure in layers containing dopaminergic cells, measured as ganglion cell layer (GCL) and inner plexiform layer (IPL) thinning (ρ = -0.29, p = 0.0021; ρ = -0.33, p = 0.00044). These relationships were not seen for the retinal nerve fiber layer that does not contain dopaminergic cells and were not seen in unaffected controls. CONCLUSION: Visual measures and retinal structure in dopaminergic layers were related to risk of PD dementia. Our findings suggest that visual measures and retinal GCL and IPL volumes may be useful to predict the risk of dementia in PD.

Automated Pupillometry Using a Prototype Binocular Optical Coherence Tomography System.

PURPOSE: To determine the test-retest reliability and diagnostic accuracy of a binocular optical coherence tomography (OCT) prototype (Envision Diagnostics, El Segundo, California, USA) for pupillometry. DESIGN: Assessment of diagnostic reliability and accuracy. METHODS: Fifty participants with relative afferent pupillary defects (RAPDs) confirmed using the swinging flashlight method (mean age 49.6 years) and 50 healthy control subjects (mean age 31.3 years) were examined. Participants twice underwent an automated pupillometry examination using a binocular OCT system that presents a stimulus and simultaneously captures OCT images of the iris-pupil plane of both eyes. Participants underwent a single examination on the RAPDx (Konan Medical, Irvine, California, USA), an automated infrared pupillometer. Pupil parameters including maximum and minimum diameter, and anisocoria were measured. The magnitude of RAPD was calculated using the log of the ratio of the constriction amplitude between the eyes. A pathological RAPD was above ±0.5 log units on both devices. RESULTS: The intraclass correlation coefficient was >0.90 for OCT-derived maximum pupil diameter, minimum pupil diameter, and anisocoria. The RAPDx had a sensitivity of 82% and a specificity of 94% for detection of RAPD whereas the binocular OCT had a sensitivity of 74% and specificity of 86%. The diagnostic accuracy of the RAPDx and binocular OCT was 88% (95% confidence interval 80%-94%) and 80% (95% confidence interval 71%-87%) respectively. CONCLUSIONS: Binocular OCT-derived pupil parameters had excellent test-retest reliability. The diagnostic accuracy of RAPD was inferior to the RAPDx and is likely related to factors such as eye movement during OCT capture. As OCT becomes ubiquitous, OCT-derived measurements may provide an efficient method of objectively quantifying the pupil responses.

Spontaneous Venous Pulsations Detected With Infrared Videography.

BACKGROUND: Assessment of spontaneous venous pulsation (SVP) is commonly undertaken to help determine whether intracranial pressure (ICP) is elevated. Previous studies using direct ophthalmoscopy or slit-lamp assessments have found that SVP is not observed in 67%-81% of subjects with normal ICP, and that interobserver agreement when grading SVP is poor. METHODS: Patients (n = 105) undergoing clinically indicated retinal OCT scans, who were all believed to have normal ICP, had 10-second infrared video recordings performed with the Heidelberg Spectralis OCT system (Heidelberg Engineering GmbH, Heidelberg, Germany). The presence and amplitude of SVP in each video was independently graded by 2 neuro-ophthalmologists. RESULTS: The 2 observers found SVP present in 97% and 98% of right eyes and in one or both eyes in 99% and 100% of subjects. Interobserver agreement was high (Cohen's kappa 0.82 for right eyes). Optic discs with a smaller cup had a significantly lower SVP amplitude (Spearman's rho = 0.22, P = 0.02). CONCLUSIONS: Infrared video is widely available in eye clinics by the use of OCT imaging systems and is substantially more sensitive in detecting SVP than traditional assessments using ophthalmoscopy. SVP is absent in as few as 1% of people with presumed normal ICP.

Association of Intracranial Pressure and Spontaneous Retinal Venous Pulsation.

Importance: A convenient and reliable method for noninvasive intracranial pressure assessments is desirable to reduce the need for invasive procedures (eg, intracranial pressure monitoring and lumbar punctures) and allow clinicians to identify and treat patients with intracranial hypertension in a timely manner. Objective: To determine whether infrared video assessment of spontaneous retinal venous pulsation is associated with intracranial pressure and is a valid tool to indicate the presence or absence of raised intracranial pressure in patients without papilledema. Design, Setting, and Participants: A single-center prospective study was conducted at a tertiary referral center between January 2017 and May 2018. Patients consecutively admitted for clinically indicated elective 24-hour invasive intracranial pressure monitoring had ophthalmic review including infrared video recording of their spontaneous venous pulsation. Two neuro-ophthalmologists, who were masked to the intracranial pressure monitoring results, independently graded the spontaneous venous pulsation (grade 0 to 3). Analysis began in June 2018. Main Outcomes and Measures: The association between simultaneously recorded intracranial pressure and spontaneous venous pulsation (binary variable: present/absent) assessed through retinal infrared video recordings was evaluated using a multiple linear regression model. Results: Of 105 patients, the mean (SD) age was 39 (14) years, and 79 (75%) were women. The mean (SD) simultaneous intracranial pressure was 1 (5) mm Hg for 91 patients (86.7%) with spontaneous venous pulsations and 13 (14) mm Hg for 14 patients (13.3%) without spontaneous venous pulsations. A multiple linear regression model adjusted for 7 potential confounders confirmed a statistically significant association between intracranial pressure and spontaneous venous pulsation (ß = -9.1; 95% CI, -13.7 to -4.6; P < .001; adjusted R2 = 0.42). Conclusions and Relevance: The absence of spontaneous venous pulsation on retinal infrared video recordings is significantly associated with higher levels of intracranial pressure and should raise the suspicion of intracranial hypertension.

The Dynamic Oval Pupil.

The dynamic oval pupil is defined and its distinction from corectopia, as well as their different clinical significance is proposed. A literature search for instances presenting this condition yielded only 20 such cases with enough clinical data. A review of these cases allows us to draw some tentative conclusions regarding the most likely anatomical location for its causative lesion and the pathophysiological mechanism responsible for its occurrence.

A Case of Synchronised Pupillary and Nasal Cycling: Evidence for a Central Autonomic Pendulum?

We previously reported that some healthy individuals show alternating anisocoria. We now describe one such individual who also exhibits a classic nasal cycle (alternating periods of nasal congestion and decongestion). We made measurements of his pupil asymmetry and nasal asymmetry at 21 different time points and found that these variables were always synchronised such that greater nasal airflow was invariably found on the same side as the larger pupil. We hypothesise that a common central oscillator may be responsible for co-modulating the sympathetic outflow to both nasal vessels and iris dilator muscles in some healthy individuals.

Dysthyroid Orbitopathy Presenting with Gaze-Evoked Amaurosis: Case Report and Review of the Literature.

BACKGROUND: Gaze-evoked amaurosis (GEA) describes visual loss associated with eccentric gaze that recovers when the eye is returned to primary position. Here we describe an unusual case of bilateral GEA as the presenting feature of dysthyroid orbitopathy. This is only the third such case to be reported in the literature and the first to feature bilateral GEA in all positions of gaze without accompanying proptosis or ophthalmoplegia. CASE PRESENTATION: A 50-year-old man who had recently commenced treatment for thyrotoxicosis presented with a 3-week history of typical GEA in both eyes in all positions of gaze. He subsequently developed a bilateral compressive optic neuropathy which was only partially responsive to high dose steroid therapy. CONCLUSION: Although an uncommon presenting feature of dysthyroid orbitopathy, GEA is an ominous symptom that may precede sight-threatening optic nerve compromise. When present, early immunosuppressive and/or decompressive treatment should be considered.

Reversal of pupillary atonia after removal of an encircling band.

: We describe a patient who developed an atonic pupil after placement of an encircling band during retinal detachment surgery. When the band was removed 18 months later, the pupil signs showed partial recovery demonstrating a degree of reversibility of the parasympathetic paresis. We speculate that in this case mechanical deformation of the sclera by the encircling band had produced a conduction block of the short posterior ciliary nerve fibers as they pass forward in the underlying suprachoroidal space.

Acquired dyschromatopsia in acute myelocytic leukaemia.

BACKGROUND: Patients with haematological malignancy are referred to the ophthalmologist either with visual symptoms or to exclude orbital or intraocular involvement after the diagnosis has been established. This report describes a patient with acute myelocytic leukaemia (AML) whose presenting symptom was dyschromatopsia. METHODS: A 52-year-old female, previously in good health, presented with a disturbance of colour vision. On examination, there was bilateral reduction in visual acuity, impaired colour vision and severely constricted visual fields. Electrophysiological testing and colour contrast sensitivity (CCS) assessment were performed. RESULTS: CCS showed bilateral threshold elevation in the tritan axis of both eyes, right worse than left. Pattern ERG showed marked macular dysfunction in the right eye, but was normal in the left eye. Full-field ERGs fell within the normal range. Pattern VEPs were reduced in the right eye, without peak time shift; flash VEPs showed bilateral delay. Investigation showed severe anaemia, and a bone marrow biopsy confirmed a diagnosis of acute AML. There was symptomatic improvement in visual acuity and colour vision following blood transfusion and initiation of chemotherapy. CONCLUSION: This appears to be the first case report of dyschromatopsia in AML with symptomatic improvement following treatment. The case lends support to previously suggested hypotheses of chromatic visual disturbance in association with presumed hypoxia.

Palinopsia as the initial manifestation of non-hodgkin's lymphoma.

A 37-year old general practitioner thought to be in good health presented to the ophthalmology department with palinopsia, headaches and transient visual obscurations. A CT scan revealed a large destructive lesion centred on the occiput and stealth guided excisional biopsy of the occipital lesion showed diffuse large B cell, Non-Hodgkin's lymphoma (NHL) infiltration. To the best of our knowledge this is only the second report of a patient with NHL presenting with palinopsia.