Visual dysfunction is a better predictor than retinal thickness for dementia in Parkinson's disease.

BACKGROUND: Dementia is a common and devastating symptom of Parkinson's disease (PD). Visual function and retinal structure are both emerging as potentially predictive for dementia in Parkinson's but lack longitudinal evidence. METHODS: We prospectively examined higher order vision (skew tolerance and biological motion) and retinal thickness (spectral domain optical coherence tomography) in 100 people with PD and 29 controls, with longitudinal cognitive assessments at baseline, 18 months and 36 months. We examined whether visual and retinal baseline measures predicted longitudinal cognitive scores using linear mixed effects models and whether they predicted onset of dementia, death and frailty using time-to-outcome methods. RESULTS: Patients with PD with poorer baseline visual performance scored lower on a composite cognitive score (ß=0.178, SE=0.05, p=0.0005) and showed greater decreases in cognition over time (ß=0.024, SE=0.001, p=0.013). Poorer visual performance also predicted greater probability of dementia (χ² (1)=5.2, p=0.022) and poor outcomes (χ² (1) =10.0, p=0.002). Baseline retinal thickness of the ganglion cell-inner plexiform layer did not predict cognitive scores or change in cognition with time in PD (ß=-0.013, SE=0.080, p=0.87; ß=0.024, SE=0.001, p=0.12). CONCLUSIONS: In our deeply phenotyped longitudinal cohort, visual dysfunction predicted dementia and poor outcomes in PD. Conversely, retinal thickness had less power to predict dementia. This supports mechanistic models for Parkinson's dementia progression with onset in cortical structures and shows potential for visual tests to enable stratification for clinical trials.

Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers.

BACKGROUND: Optic neuropathy is a near ubiquitous feature of Friedreich's ataxia (FRDA). Previous studies have examined varying aspects of the anterior and posterior visual pathways but none so far have comprehensively evaluated the heterogeneity of degeneration across different areas of the retina, changes to the macula layers and combined these with volumetric MRI studies of the visual cortex and frataxin level. METHODS: We investigated 62 genetically confirmed FRDA patients using an integrated approach as part of an observational cohort study. We included measurement of frataxin protein levels, clinical evaluation of visual and neurological function, optical coherence tomography to determine retinal nerve fibre layer thickness and macular layer volume and volumetric brain MRI. RESULTS: We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. CONCLUSION: Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy.

OBJECTIVE: The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. METHODS: We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. RESULTS: At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. INTERPRETATION: Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

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.

A patient-reported outcome measure for patients with pituitary adenoma undergoing transsphenoidal surgery.

PURPOSE: Pituitary adenomas affect patients' quality-of-life (QoL) across several domains, with long-term implications even following gross-total resection or disease remission. While clinical outcomes can assess treatment efficacy, they do not capture variations in QoL. We present the development and validation of a patient reported outcome measure (PROM) for patients with pituitary adenomas undergoing transsphenoidal surgery. METHODS: The COSMIN checklist informed the development of the pituitary outcome score (POS). Consecutive patients undergoing surgical treatment for suspected pituitary adenoma at a single centre were included prospectively. An expert focus group and patient interviews informed item generation. Item reduction was conducted through exploratory factor analysis and expert consensus, followed by assessment of the tool's validity, reliability, responsiveness, and interpretability. RESULTS: 96 patients with a median age of 50 years validated the POS. The final questionnaire included 25 questions with four subscales: EQ-5D-5L-QoL, Visual Symptoms, Endocrine Symptoms and Nasal Symptoms. CONCLUSION: The POS is the first validated PROM for patients undergoing transsphenoidal surgery for a pituitary adenoma. This PROM could be integrated into contemporary practice to provide patient-centred outcomes assessment for this patient group, aligning more closely with patient objectives.

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.

Retinal Architecture in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Insights into Disease Pathogenesis and Biomarkers.

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. OBJECTIVE: To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. METHODS: We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n = 196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. RESULTS: Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 µm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. CONCLUSIONS: Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society.

Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease.

BACKGROUND: Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end-organ damage. OBJECTIVE: To identify a biomarker for neurological involvement in WD. METHODS: Neuronal and glial-specific proteins were measured in plasma samples from 40 patients and 38 age-matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non-adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded. RESULTS: Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients. CONCLUSION: NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240.

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.

Paradoxical response of intracranial pressure to shunt valve setting adjustments.

BACKGROUND: The hydrodynamics of cerebrospinal fluid shunts have been described in vitro; however, knowledge on the response of intracranial pressure (ICP) to valve settings adjustments in vivo is limited. This study describes the effect of adjusting the shunt valve setting on ICP in a cohort of patients with complex symptom management. METHOD: Single-centre retrospective observational study. Patients who underwent ICP-guided valve setting adjustments during 24-h continuous ICP monitoring, between 2014 and 2019, were included. Patients with suspected shunt malfunction were excluded. Median night ICP before and after the valve adjustments were compared (Δ night ICP). The responses of ICP to valve adjustment were divided into 3 different groups as follows: expected, paradoxical and no response. The frequency of the paradoxical response and its potential predicting factors were investigated. RESULTS: Fifty-one patients (37 females, 14 males, mean age 38 years) receiving 94 valve setting adjustments met the study inclusion criteria. Patients' underlying conditions were most commonly hydrocephalus (47%) or idiopathic intracranial hypertension (43%). The response of ICP to valve setting adjustments was classified as 'expected' in 54 cases (57%), 'paradoxical' in 17 cases (18%) and 'no effect' (Δ night ICP < 1 mmHg) in 23 cases (24%). There was a significant correlation between the Δ night ICP and the magnitude of valve setting change in both the investigated valves (Miethke ProGAV, p = 0.01 and Medtronic Strata, p = 0.02). CONCLUSIONS: Paradoxical ICP changes can occur after shunt valve setting adjustments. This observation should be taken into account when performing ICP-guided valve adjustments and is highly relevant for the future development of "smart" shunt systems.

Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disorder caused by mutations in the SACS gene. Thickened retinal nerve fibres visible on fundoscopy have previously been described in these patients; however, thickening of the retinal nerve fibre layer as demonstrated by optical coherence tomography appears to be a more sensitive and specific feature. To test this observation, we assessed 292 individuals (191 patients with ataxia and 101 control subjects) by peripapillary time-domain optical coherence tomography. The patients included 146 with a genetic diagnosis of ataxia (17 autosomal spastic ataxia of Charlevoix-Saguenay, 59 Friedreich's ataxia, 53 spinocerebellar ataxias, 17 other genetically confirmed ataxias) and 45 with cerebellar ataxia of unknown cause. The controls included 13 asymptomatic heterozygotes for SACS mutations and 88 unaffected controls. The cases with autosomal recessive spastic ataxia of Charlevoix-Saguenay included 11 previously unpublished SACS mutations, of which seven were nonsense and four missense mutations. Most patients were visually asymptomatic and had no previous history of ophthalmic complaints and normal or near normal visual test results. None had visual symptoms directly attributable to the retinal changes. Twelve of the 17 cases (70.6%) had thickened retinal nerve fibres visible on fundoscopy. All patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay had thickening of the peripapillary retinal nerve fibre layer on optical coherence tomography, whereas all the remaining cases and controls except one showed normal or reduced average peripapillary retinal nerve fibre layer thickness on optical coherence tomography. We propose a cut-off value of 119 µm in average peripapillary retinal nerve fibre layer thickness, which provides a sensitivity of 100% and specificity of 99.4% amongst patients affected with ataxia. This is the largest cohort of patients with this condition to undergo systematic evaluation by optical coherence tomography. This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Visualization of thickened retinal fibres by direct fundoscopy is less sensitive. We therefore advocate the use of this technique in the assessment of possible cases of this condition.

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.

A Rare Case of Bilateral Optic Neuritis and Guillain-Barré Syndrome Post Mycoplasma pneumoniae Infection.

Neurological complications are the most commonly encountered extra-pulmonary manifestation of infection with Mycoplasma pneumoniae (M. pneumoniae). Here the authors report the case of a 39-year-old woman who was admitted with acute-onset bilateral visual loss coinciding with ascending numbness. Clinical examination, neurological imaging, and nerve conduction studies revealed a syndrome of bilateral optic neuritis and Guillain-Barré syndrome (GBS). Serological testing confirmed recent exposure to M. pneumoniae. The patient did not experience any clinical benefit with pulsed intravenous methylprednisolone but demonstrated marked clinical and radiological improvement following 5 days of plasma exchange. This report will explore the diagnostic and therapeutic approach to patients with neuro-ophthalmological and neurological complications of M. pneumoniae infection in addition to discussing previously encountered cases.

Extra-ocular muscle MRI in genetically-defined mitochondrial disease.

OBJECTIVES: Conventional and quantitative MRI was performed in patients with chronic progressive external ophthalmoplegia (CPEO), a common manifestation of mitochondrial disease, to characterise MRI findings in the extra-ocular muscles (EOMs) and investigate whether quantitative MRI provides clinically relevant measures of disease. METHODS: Patients with CPEO due to single mitochondrial DNA deletions were compared with controls. Range of eye movement (ROEM) measurements, peri-orbital 3 T MRI T1-weighted (T1w) and short-tau-inversion-recovery (STIR) images, and T2 relaxation time maps were obtained. Blinded observers graded muscle atrophy and T1w/STIR hyperintensity. Cross-sectional areas and EOM mean T2s were recorded and correlated with clinical parameters. RESULTS: Nine patients and nine healthy controls were examined. Patients had reduced ROEM (patients 13.3°, controls 49.3°, p < 0.001), greater mean atrophy score and increased T1w hyperintensities. EOM mean cross-sectional area was 43 % of controls and mean T2s were prolonged (patients 75.6 ± 7.0 ms, controls 55.2 ± 4.1 ms, p < 0.001). ROEM correlated negatively with EOM T2 (rho = -0.89, p < 0.01), whilst cross-sectional area failed to correlate with any clinical measures. CONCLUSIONS: MRI demonstrates EOM atrophy, characteristic signal changes and prolonged T2 in CPEO. Correlation between elevated EOM T2 and ROEM impairment represents a potential measure of disease severity that warrants further evaluation. KEY POINTS: Chronic progressive external ophthalmoplegia is a common clinical manifestation of mitochondrial disease. • Existing extra-ocular muscle MRI data in CPEO reports variable radiological findings. MRI confirmed EOM atrophy and characteristic signal changes in CPEO. EOM T2 was significantly elevated in CPEO and correlated negatively with ocular movements. EOM T2 represents a potential quantitative measure of disease severity in CPEO.

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.