Odour discrimination and identification as a biomarker of long-term disability worsening in multiple sclerosis.

BACKGROUND: Odour discrimination and identification (DI) are markers associated with disability worsening and neuroaxonal damage in multiple sclerosis (MS). OBJECTIVE: The main objective of this research is to investigate whether longitudinal change of DI predicts long-term MS disease course. METHODS: This is a 6-year prospective longitudinal study on MS patients at the MS Clinic Innsbruck. Clinical, bi-annual visits assessed patients' history and Expanded Disability Status Scale (EDSS) score. DI and cognitive function were assessed at baseline (BL), Year 1 (Y1), Year 2 (Y2) and Year 6 (Y6) by the 'Sniffin' Sticks'/Symbol Digit Modalities Test. RESULTS: Around 92 of 139 patients were available for Y6 follow-up. Mean DI scores significantly decreased over time (BL = 27.8, Y1 = 27.5, Y2 = 26.3 and Y6 = 26.3; p < 0.001) and negatively correlated with patients' age (rs = -0.120, p = 0.032) and disease duration (rs = -0.103, p = 0.041). Multivariable regression analyses revealed that lower absolute DI scores and larger DI score loss over time were associated with higher probability of EDSS worsening (per -1 point: hazard ratio (HR) = 1.40 (1.16-1.68) and 2.34 (1.27-4.21)), progression independent of relapse activity (PIRA) (HR = 1.49 (1.20-1.85) and 2.22 (1.33-3.31)) and cognitive deterioration (HR = 1.75 (1.35-2.27) and 4.29 (1.26-2.84)) at Y6, but not with time to first relapse. CONCLUSION: Odour DI is an irreversible marker of neuroaxonal damage, associated with PIRA, cognitive deterioration and EDSS worsening.

Retinal layer thinning for monitoring disease-modifying treatment in relapsing multiple sclerosis-Evidence for applying a rebaselining concept.

BACKGROUND: Employing a rebaselining concept may reduce noise in retinal layer thinning measured by optical coherence tomography (OCT). METHODS: From an ongoing prospective observational study, we included patients with relapsing multiple sclerosis (RMS), who had OCT scans at disease-modifying treatment (DMT) start (baseline), 6-12 months after baseline (rebaseline), and ⩾12 months after rebaseline. Mean annualized percent loss (aL) rates (%/year) were calculated both from baseline and rebaseline for peripapillary-retinal-nerve-fiber-layer (aLpRNFLbaseline/aLpRNFLrebaseline) and macular-ganglion-cell-plus-inner-plexiform-layer (aLGCIPLbaseline/aLGCIPLrebaseline) by mixed-effects linear regression models. RESULTS: We included 173 RMS patients (mean age 31.7 years (SD 8.8), 72.8% female, median disease duration 15 months (12-94) median baseline-to-last-follow-up-interval 37 months (18-71); 56.6% moderately effective DMT (M-DMT), 43.4% highly effective DMT (HE-DMT)). Both mean aLpRNFLbaseline and aLGCIPLbaseline significantly increased in association with relapse (0.51% and 0.26% per relapse, p < 0.001, respectively) and disability worsening (1.10% and 0.48%, p < 0.001, respectively) before baseline, but not with DMT class. Contrarily, neither aLpRNFLrebaseline nor aLGCIPLrebaseline was dependent on relapse or disability worsening before baseline, while HE-DMT significantly lowered aLpRNFLrebaseline (by 0.31%, p < 0.001) and aLGCIPLrebaseline (0.25%, p < 0.001) compared with M-DMT. CONCLUSIONS: Applying a rebaselining concept significantly improves differentiation of DMT effects on retinal layer thinning by avoiding carry-over confounding from previous disease activity.

An interdisciplinary integrated specialized one-stop outpatient clinic for idiopathic intracranial hypertension-a comprehensive assessment of clinical outcome.

BACKGROUND AND PURPOSE: Management of idiopathic intracranial hypertension (IIH) is complex requiring multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges for healthcare professionals and patients. Thus, an interdisciplinary integrated outpatient clinic for IIH (comprising neurology, neuroophthalmology, neuroradiology, neurosurgery and endocrinology) was established with central coordination and a one-stop concept. Here, the aim was to evaluate the effects of this one-stop concept on objective clinical outcome. METHODS: In a retrospective cohort study, the one-stop era with integrated care (IC) (1 July 2021 to 31 December 2022) was compared to a reference group receiving standard care (SC) (1 July 2018 to 31 December 2019) regarding visual impairment/worsening and headache improvement/freedom 6 months after diagnosis. Multivariate binary logistic regression models were used to adjust for confounders. RESULTS: Baseline characteristics of the IC group (n = 85) and SC group (n = 81) were comparable (female 90.6% vs. 90.1%; mean age 33.6 vs. 32.8 years; median body mass index 31.8 vs. 33.0; median cerebrospinal fluid opening pressure 32 vs. 34 cmH2O; at diagnosis, visual impairment was present in 71.8% vs. 69.1% and chronic headache in 55.3% vs. 56.8% in IC vs. SC). IC was associated with a higher likelihood of achieving both headache improvement (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.52-4.33, p < 0.001) and headache freedom (OR 1.75, 95% CI 1.11-3.09, p = 0.031). Regarding the risk of visual impairment and visual worsening IC was superior numerically but not statistically significantly (OR 0.87, 95% CI 0.69-1.16, p = 0.231, and OR 0.67, 95% CI 0.41-1.25, p = 0.354). CONCLUSIONS: Interdisciplinary integrated care of IIH is favourably associated with headache outcomes and potentially also visual outcomes.

Treating to target in multiple sclerosis: Do we know how to measure whether we hit it?

BACKGROUND AND PURPOSE: The rapidly evolving landscape of effective treatment options in multiple sclerosis has led to a shift of treatment objectives towards a treat-to-target approach aiming to suppress disease activity below the level of detectability early during the disease. To enable treat-to-target, a thorough reappraisal of available outcome measures with respect to their ability in this regard is required. METHODS: To that end, we conducted a comprehensive systematic literature review of more than 1000 studies using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 methodology focusing on underlying evidence as well as utility and implementability in clinical practice. RESULTS: From there, we propose a set of measurable outcomes for everyday routine clinical practice as well as advanced/aspirational measurables requiring additional resources. We also outline remaining knowledge/technology gaps that need to be overcome to enable a treat-to-target approach. CONCLUSIONS: This work provides the basis for an evidence-based definition of outcome targets for relevant stakeholders and regulatory authorities.

Therapeutic effect of a single lumbar puncture in idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by increased intracranial pressure. Whilst lumbar puncture (LP) is necessary for the diagnosis of IIH, its therapeutic effect remains unclear. Our aim was to evaluate the therapeutic effect of a single LP in people with IIH (pwIIH). METHODS: In this prospective observational study, we analysed short-term neurological and ophthalmological outcomes in pwIIH before, one (D1) and seven days (D7) after the LP. The primary outcome was the change in papilledema degree from baseline. Secondary outcomes included visual outcomes, morphological changes in optical coherence tomography (peripapillary retinal nerve fibre layer [pRNFL] thickness and ganglion cell layer [GCL] volume) and transbulbar sonography (arachnoid optic nerve sheath diameter [AONSD]), and headache outcomes (peak and median headache severity and burden related to headache). RESULTS: We included 30 pwIIH (mean age 32.8 years [SD 8.4], 93.3% female, median cerebrospinal fluid [CSF] opening pressure 33.0 cmCSF [IQR 26.9-35.3], median body mass index (BMI) 34.8 kg/m2 [IQR 30.9-40.9]). The median papilledema grading at baseline was 2 (Friedman DI (1999) Pseudotumor cerebri. Neurosurg Clin N Am 10(4):609-621 viii); (Mollan SP, Aguiar M, Evison F, Frew E, Sinclair AJ (2019) The expanding burden of idiopathic intracranial hypertension. Eye Lond Engl 33(3):478-485); (Ab D, Gt L, Nj V, Sl G, Ml M, Nj N et al. (2007) Profiles of obesity, weight gain, and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri). Am J Ophthalmol [Internet]. Apr [cited 2024 Jun 2];143(4). https://pubmed.ncbi.nlm.nih.gov/17386271/ ) and was significantly reduced at D7 (2 [1-2], p = 0.011). Median pRNFL thickness had decreased significantly at D7 (-9 µm [-62.5, -1.3], p = 0.035), with pRNFL thickness at baseline being associated with the pRNFL change (F(1,11) = 18.79, p = 0.001). Mean AONSD had decreased significantly at both D1 (-0.74 mm [0.14], p < 0.001) and D7 (-0.65 mm [0.17], p = 0.01), with AONSD at baseline being associated with the change in AONSD at both time points (D1: ß= -0.89, 95% CI -1.37, -0.42, p = 0.002; D7: ß= -0.85, 95% CI -1.42, -0.28, p = 0.007). Peak headache severity was slightly lower at D7 (-1/10 [-3, 0], p = 0.026), whereas median headache severity and headache burden remained unchanged. CONCLUSIONS: This short-term follow-up study in pwIIH undergoing a single LP suggests a moderate effect on ophthalmological but not headache outcomes. The usefulness of LP as a therapeutic measure in IIH remains controversial and should likely be reserved for patients with limited treatment options, e.g., in pregnancy or intolerability to medication.

Plasma calcitonin gene-related peptide levels in idiopathic intracranial hypertension: an exploratory study.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a debilitating condition characterized by increased intracranial pressure often presenting with chronic migraine-like headache. Calcitonin gene-related peptide (CGRP) plays an important pathophysiological role in primary headaches such as migraine, whilst its role in IIH has not yet been established. METHODS: This longitudinal exploratory study included patients with IIH, episodic migraine (EM) in a headache-free interval and healthy controls (HC). Blood samples were collected from a cubital vein and plasma CGRP (pCGRP) levels were measured by standardized ELISA. RESULTS: A total of 26 patients with IIH (mean age 33.2 years [SD 9.2], 88.5% female, median BMI 34.8 kg/m2 [IQR 30.0-41.4]), 30 patients with EM (mean age 27.6 years [7.5], 66.7% female) and 57 HC (mean age 25.3 years [5.2], 56.1% female) were included. pCGRP levels displayed a wide variation in IIH as well as in EM and HC on a group-level. Within IIH, those with migraine-like headache had significantly higher pCGRP levels than those with non-migraine-like headache (F(2,524) = 84.79; p < 0.001) and headache absence (F(2,524) = 84.79; p < 0.001) throughout the observation period, explaining 14.7% of the variance in pCGRP levels. CGRP measurements showed strong intraindividual agreement in IIH (ICC 0.993, 95% CI 0.987-0.996, p < 0.001). No association was found between pCGRP levels and ophthalmological parameters. CONCLUSIONS: Although interindividual heterogeneity of pCGRP levels is generally high, migraine-like headache seems to be associated with higher pCGRP levels. CGRP may play a role in the headache pathophysiology at least in a subgroup of IIH.

An interdisciplinary integrated specialized one-stop outpatient clinic for idiopathic intracranial hypertension - a comprehensive assessment of patient satisfaction.

BACKGROUND: Management of idiopathic intracranial hypertension (IIH) is complex requiring contributions from multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges. To meet those challenges, we established an interdisciplinary integrated outpatient clinic for IIH with a central coordination and a one-stop concept. Here, we aimed to evaluate effects of this one-stop concept on subjective patient satisfaction and economic outcome in patients with IIH. METHODS: In a retrospective cohort study, we compared the one-stop era with integrated care (IC, 1-JUL-2021 to 31-DEC-2022) to a reference group receiving standard care (SC, 1-JUL-2018 to 31-DEC-2019) regarding subjective patient satisfaction (assessed by the Vienna Patient Inventory). Multivariable binary linear regression models were used to adjust for confounders. RESULTS: Baseline characteristics of the IC group (n = 85) and SC group (n = 81) were comparable (female: 90.6% vs. 90.1%; mean age: 33.6 vs. 32.8 years, educational level: ≥9 years of education 60.0% vs. 59.3%; located in Vienna 75.3% vs. 76.5%). Compared to SC, management within IC concept was associated with statistically significantly higher subjective patient satisfaction (beta = 0.93; p < 0.001) with the strongest effects observed in satisfaction with treatment accessibility and availability (beta = 2.05; p < 0.001). Subgroup analyses of patients with migration background and language barrier consistently indicated stronger effects of IC in these groups. CONCLUSIONS: Interdisciplinary integrated management of IIH statistically significantly and clinically meaningfully improves patient satisfaction - particularly in socioeconomically underprivileged patient groups. Providing structured central coordination to facilitate and improve access to interdisciplinary management provides means to further improve outcome.

An interdisciplinary integrated specialized one-stop outpatient clinic for idiopathic intracranial hypertension - an assessment of sick leave, presenteeism, and health care utilization.

BACKGROUND: Management of idiopathic intracranial hypertension (IIH) is complex requiring contributions from multiple specialized disciplines. In practice, this creates considerable organizational and communicational challenges. To meet those challenges, we established an interdisciplinary integrated outpatient clinic for IIH with a central coordination and a one-stop- concept. Here, we aimed to evaluate effects of this concept on sick leave, presenteeism, and health care utilization. METHODS: In a retrospective cohort study, we compared the one-stop era with integrated care (IC, 1-JUL-2021 to 31-DEC-2022) to a reference group receiving standard care (SC, 1-JUL-2018 to 31-DEC-2019) regarding economic outcome parameters assessed over 6 months. Multivariate binary logistic regression models were used to adjust for confounders. RESULTS: Baseline characteristics of the IC group (n = 85) and SC group (n = 81) were comparable (female: 90.6% vs. 90.1%; mean age: 33.6 vs. 32.8 years, educational level: ≥9 years of education 60.0% vs. 59.3%; located in Vienna 75.3% vs. 76.5%). Compared to SC, the IC group showed significantly fewer days with sick leave or presenteeism (-5 days/month), fewer unscheduled contacts for IIH-specific problems (-2.3/month), and fewer physician or hospital contacts in general (-4.1 contacts/month). Subgroup analyses of patients with migration background and language barrier consistently indicated stronger effects of the IC concept in these groups. CONCLUSIONS: Interdisciplinary integrated management significantly improves the burden of IIH in terms of sick leave, presenteeism and healthcare consultations - particularly in socioeconomically underprivileged patient groups.

The additive value of complementing diagnostic idiopathic intracranial hypertension criteria by MRI - an external validation study.

BACKGROUND: Recently, diagnostic criteria including a standardized MRI criterion were presented to identify patients suffering from idiopathic intracranial hypertension (IIH) proposing that IIH might be defined by two out of three objective findings (papilledema, ≥ 25 cm cerebrospinal fluid opening pressure (CSF-OP) and ≥ 3/4 neuroimaging signs). METHODS: To provide independent external validation, we retrospectively applied the proposed diagnostic criteria to our cohort of patients with clinical suspicion of IIH from the Vienna IIH database. Neuroimaging was reevaluated for IIH signs according to standardized definitions by a blinded expert neuroradiologist. We determined isolated diagnostic accuracy of the neuroimaging criterion (≥ 3/4 signs) as well as overall accuracy of the new proposed criteria. RESULTS: We included patients with IIH (n = 102) and patients without IIH (no-IIH, n = 23). Baseline characteristics were balanced between IIH and no-IIH groups, but papilledema and CSF-OP were significantly higher in IIH. For the presence of ≥ 3/4 MRI signs, sensitivity was 39.2% and specificity was 91.3% with positive predictive value (PPV) of 95.2% and negative predictive value (NPV) 25.3%. Reclassifying our cohort according to the 2/3 IIH definition correctly identified 100% of patients without IIH, with definite IIH and suggested to have IIH without papilledema by Friedman criteria, respectively. CONCLUSION: The standardized neuroimaging criteria are easily applicable in clinical routine and provide moderate sensitivity and excellent specificity to identify patients with IIH. Defining IIH by 2/3 criteria significantly simplifies diagnosis without compromising accuracy.

Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis.

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3 T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening.

Association of paramagnetic rim lesions and retinal layer thickness in patients with multiple sclerosis.

BACKGROUND: Paramagnetic rim lesions (PRLs) are chronic active lesions associated with a more severe disease course in multiple sclerosis (MS). Retinal layer thinning measured by optical coherence tomography (OCT) is a biomarker of neuroaxonal damage associated with disability progression in MS. OBJECTIVE: We aimed to determine a potential association between OCT parameters (peripapillary retinal nerve fiber layer (pRNFL) ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL) thickness), and PRLs in patients with MS (pwMS). METHODS: In this cross-sectional retrospective study, we included pwMS with both 3T brain MRI and an OCT scan. Regression models were calculated with OCT parameters (pRNFL, GCIPL, INL) as dependent variables, and the number of PRLs as an independent variable adjusted for covariates. RESULTS: We analyzed data from 107 pwMS (mean age 34.7 years (SD 10.9), 64.5% female, median disease duration 6 years (IQR 1-13), median EDSS 1.5 (range 0-6.5)). Higher number of PRLs was associated with lower pRNFL (ß = -0.18; 95% CI -0.98, -0.03; p = 0.038) and GCIPL thickness (ß = -0.21; 95% CI -0.58, -0.02; p = 0.039). CONCLUSION: The association between higher number of PRLs and lower pRNFL and GCIPL thicknesses provides additional evidence that pwMS with PRLs are affected by a more pronounced neurodegenerative process.

Paramagnetic rim lesions lead to pronounced diffuse periplaque white matter damage in multiple sclerosis.

BACKGROUND: Paramagnetic rim lesions (PRLs) are an imaging biomarker in multiple sclerosis (MS), associated with a more severe disease. OBJECTIVES: To determine quantitative magnetic resonance imaging (MRI) metrics of PRLs, lesions with diffuse susceptibility-weighted imaging (SWI)-hypointense signal (DSHLs) and SWI-isointense lesions (SILs), their surrounding periplaque area (PPA) and the normal-appearing white matter (NAWM). METHODS: In a cross-sectional study, quantitative MRI metrics were measured in people with multiple sclerosis (pwMS) using the multi-dynamic multi-echo (MDME) sequence post-processing software "SyMRI." RESULTS: In 30 pwMS, 59 PRLs, 74 DSHLs, and 107 SILs were identified. Beside longer T1 relaxation times of PRLs compared to DSHLs and SILs (2030.5 (1519-2540) vs 1615.8 (1403.3-1953.5) vs 1199.5 (1089.6-1334.6), both p < 0.001), longer T1 relaxation times were observed in the PRL PPA compared to the SIL PPA and the NAWM but not the DSHL PPA. Patients with secondary progressive multiple sclerosis (SPMS) had longer T1 relaxation times in PRLs compared to patients with late relapsing multiple sclerosis (lRMS) (2394.5 (2030.5-3040) vs 1869.3 (1491.4-2451.3), p = 0.015) and also in the PRL PPA compared to patients with early relapsing multiple sclerosis (eRMS) (982 (927-1093.5) vs 904.3 (793.3-958.5), p = 0.013). CONCLUSION: PRLs are more destructive than SILs, leading to diffuse periplaque white matter (WM) damage. The quantitative MRI-based evaluation of the PRL PPA could be a marker for silent progression in pwMS.

Impact of rater experience and referral question on detecting magnetic resonance imaging features of idiopathic intracranial hypertension.

BACKGROUND AND PURPOSE: In idiopathic intracranial hypertension (IIH), magnetic resonance imaging (MRI) features are promising diagnostic markers, but the impact of rater experience and the specific referral question is unknown. METHODS: From the Vienna Idiopathic Intracranial Hypertension database, patients were included with definitive IIH and routine cranial MRI performed during diagnostic work-up. Frequencies of partial empty sella (ES), optic nerve sheath distension (ONSD), optic nerve tortuosity (ONT), posterior globe flattening (PGF) and transverse sinus stenosis (TSS) were compared in three settings: (i) real-world rating, (ii) junior neuroradiologist without special IIH training and (iii) senior neuroradiologist with experience in IIH imaging (gold standard). RESULTS: Magnetic resonance imaging scans of 84 IIH patients (88% female, mean age 33.5 years) were evaluated. By gold standard, ONSD was the most frequent (64.3%) followed by TSS (60.0%), ONT (46.4%), ES (44.4%) and PGF (23.8%). Compared to the gold standard, IIH features were described significantly less frequently in routine MRI reports (ONSD 28.6%, ONT 13.1%, PGF 4.8%, TSS 42.9%, p < 0.01 respectively) except for ES (42.9%, p = 0.9). A specific referral question regarding IIH increased detection rates in routine reports, but rates remained significantly lower than by gold standard. In contrast, a rating by a neuroradiologist without special training produced significantly higher frequencies of ONSD (81.0%, p < 0.01) and ONT (60.7%, p < 0.01) but not of ES (47.6%), PGF (29.8%) and TSS (68.1%). CONCLUSIONS: Idiopathic intracranial hypertension MRI features are underestimated in routine MRI reports and partly overcalled by less experienced neuroradiologists, driven by features less well known or methodologically difficult. Reevaluation of MRI scans by an experienced rater (and to a lesser degree a specific referral question) improves diagnostic accuracy.

Reported neurological symptoms after severe acute respiratory syndrome coronavirus type 2 infection: A systematic diagnostic approach.

BACKGROUND AND PURPOSE: Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose, and document neurological complaints potentially associated with a prior SARS-CoV-2 infection. METHODS: The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semistandardized interviewing about symptoms with reported onset after SARS-CoV-2 infection, neurological examination, and comprehensive diagnostic workup. RESULTS: Reported new onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID-19) disease course (84%) and reported comorbidities (71%), of which the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID-19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, or electrophysiological or imaging assessments in the majority of patients (n = 143, 91.7%). Neuropsychological assessment of a subgroup of patients (n = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common. CONCLUSIONS: In this systematic registry, we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS-CoV-2 infection. Structural neurological findings were rare. We also suspect a link between the growing burden of the COVID-19 pandemic on personal lives and the increase in reported neurological and psychiatric complaints.

Retinal layer thickness predicts disability accumulation in early relapsing multiple sclerosis.

BACKGROUND AND PURPOSE: This study was undertaken to investigate baseline peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness for prediction of disability accumulation in early relapsing multiple sclerosis (RMS). METHODS: From a prospective observational study, we included patients with newly diagnosed RMS and obtained spectral-domain optical coherence tomography scan within 90 days after RMS diagnosis. Impact of pRNFL and GCIPL thickness for prediction of disability accumulation (confirmed Expanded Disability Status Scale [EDSS] score ≥ 3.0) was tested by multivariate (adjusted hazard ratio [HR] with 95% confidence interval [CI]) Cox regression models. RESULTS: We analyzed 231 MS patients (mean age = 30.3 years, SD = 8.1, 74% female) during a median observation period of 61 months (range = 12-93). Mean pRNFL thickness was 92.6 µm (SD = 12.1), and mean GCIPL thickness was 81.4 µm (SD = 11.8). EDSS ≥ 3 was reached by 28 patients (12.1%) after a median 49 months (range = 9-92). EDSS ≥ 3 was predicted with GCIPL < 77 µm (HR = 2.7, 95% CI = 1.6-4.2, p < 0.001) and pRNFL thickness ≤ 88 µm (HR = 2.0, 95% CI = 1.4-3.3, p < 0.001). Higher age (HR = 1.4 per 10 years, p < 0.001), incomplete remission of first clinical attack (HR = 2.2, p < 0.001), ≥10 magnetic resonance imaging (MRI) lesions (HR = 2.0, p < 0.001), and infratentorial MRI lesions (HR = 1.9, p < 0.001) were associated with increased risk of disability accumulation, whereas highly effective disease-modifying treatment was protective (HR = 0.6, p < 0.001). Type of first clinical attack and presence of oligoclonal bands were not significantly associated. CONCLUSIONS: Retinal layer thickness (GCIPL more than pRNFL) is a useful predictor of future disability accumulation in RMS, independently adding to established markers.

Idiopathic intracranial hypertension presenting with migraine phenotype is associated with unfavorable headache outcomes.

OBJECTIVE: To assess the prognostic impact of migraine headache in idiopathic intracranial hypertension (IIH). BACKGROUND: Migraine headache is common in IIH, but it is unclear whether it has prognostic relevance. METHODS: We investigated patients with IIH from the Vienna-IIH-database and differentiated migraine (IIH-MIG) from non-migraine headache (IIH-nonMIG) and without headache (IIH-noHA). Using multivariable models, we analyzed the impact of IIH-MIG on headache and visual outcomes 12 months after diagnosis. RESULTS: Among 97 patients (89% female, mean [SD] age 32.9 [11.1] years, median body mass index 32.0 kg/m2 , median cerebrospinal fluid opening pressure 310 mm), 46% were assigned to IIH-MIG, 37% to IIH-nonMIG (11% tension-type, 26% unclassifiable), and 17% to IIH-noHA. Overall, headache improvement was achieved in 77% and freedom of headache in 28%. The IIH-MIG group showed significantly lower rates for headache improvement (67% vs. 89% in IIH-nonMIG, p = 0.019) and freedom of headache (11% vs. 33% in IIH-nonMIG and 63% in IIH-noHA, p = 0.015). These differences persisted when only analyzing patients with resolved papilledema at follow-up. In contrast, visual worsening was significantly less common in IIH-MIG (9% vs. 28% in IIH-nonMIG and 31% in IIH-noHA, p = 0.045). In multivariable models, IIH-MIG was associated with a significantly lower likelihood of achieving headache improvement (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.40-0.78, p < 0.001) and freedom of headache (OR 0.29, 95% CI 0.12-0.46, p < 0.001), but also a lower risk for visual worsening (OR 0.26, 95% CI 0.04-0.82, p < 0.001). CONCLUSIONS: In IIH, migraine headache is associated with unfavorable outcomes for headache, even when papilledema has resolved, and possibly favorable visual outcome.

Treatment with GLP-1 receptor agonists is associated with significant weight loss and favorable headache outcomes in idiopathic intracranial hypertension.

BACKGROUND: In idiopathic intracranial hypertension (IIH), sustained weight loss is the main pillar in modifying disease course, whereby glucagon-like peptide-1 receptor agonists (GLP-1-RAs) could present an attractive treatment option. METHODS: In this open-label, single-center, case-control pilot study, patients with IIH (pwIIH) and a body mass index (BMI) of ≥ 30 kg/m2 were offered to receive a GLP-1-RA (semaglutide, liraglutide) in addition to the usual care weight management (UCWM). Patients electing for UCWM only served as a control group matched for age-, sex- and BMI (1:2 ratio). The primary endpoint was the percentage weight loss at six months (M6) compared to baseline. Secondary endpoints included the rate of patients with a weight loss of ≥ 10%, monthly headache days (MHD), the rate of patients with a ≥ 30% and ≥ 50% reduction in MHD, visual outcome parameters, and adverse events (AEs). RESULTS: We included 39 pwIIH (mean age 33.6 years [SD 8.0], 92.3% female, median BMI 36.3 kg/m2 [IQR 31.4-38.3]), with 13 patients being treated with GLP-1-RAs. At M6, mean weight loss was significantly higher in the GLP-1-RA group (-12.0% [3.3] vs. -2.8% [4.7]; p < 0.001). Accordingly, weight loss of ≥ 10% was more common in this group (69.2% vs. 4.0%; p < 0.001). Median reduction in MHD was significantly higher in the GLP-1-RA group (-4 [-10.5, 0.5] vs. 0 [-3, 1]; p = 0.02), and the 50% responder rate was 76.9% vs. 40.0% (p = 0.04). Visual outcome parameters did not change significantly from baseline to M6. Median reduction in acetazolamide dosage was significantly higher in the GLP-1-RA group (-16.5% [-50, 0] vs. 0% [-25, 50]; p = 0.04). AEs were mild or moderate and attributed to gastrointestinal symptoms in 9/13 patients. None of the AEs led to premature treatment discontinuation. CONCLUSIONS: This open-label, single-center pilot study suggests that GLP-1-RAs are an effective and safe treatment option for achieving significant weight loss with a favorable effect on headache, leading to reduced acetazolamide dosage in pwIIH.

MRI features of idiopathic intracranial hypertension are not prognostic of visual and headache outcome.

BACKGROUND: In idiopathic intracranial hypertension (IIH), certain MRI features are promising diagnostic markers, but whether these have prognostic value is currently unknown. METHODS: We included patients from the Vienna-Idiopathic-Intracranial-Hypertension (VIIH) database with IIH according to Friedman criteria and cranial MRI performed at diagnosis. Presence of empty sella (ES), perioptic subarachnoid space distension (POSD) with or without optic nerve tortuosity (ONT), posterior globe flattening (PGF) and transverse sinus stenosis (TSS) was assessed and multivariable regression models regarding visual outcome (persistent visual impairment/visual worsening) and headache outcome (headache improvement/freedom of headache) were fitted. RESULTS: We included 84 IIH patients (88.1% female, mean age 33.5 years, median body mass index 33.7). At baseline, visual impairment was present in 70.2% and headache in 84.5% (54.8% chronic). Persistent visual impairment occurred in 58.3%, visual worsening in 13.1%, headache improvement was achieved in 83.8%, freedom of headache in 26.2%. At least one MRI feature was found in 78.6% and 60.0% had ≥3 features with POSD most frequent (64.3%) followed by TSS (60.0%), ONT (46.4%), ES (44.0%) and PGF (23.8%). In multivariable models, there was no association of any single MRI feature or their number with visual impairment, visual worsening, headache improvement or freedom. Visual impairment at baseline predicted persistent visual impairment (odds ratio 6.3, p<0.001), but not visual worsening. Chronic headache at baseline was significantly associated with lower likelihood of headache freedom (odds ratio 0.48, p=0.013), but not with headache improvement. CONCLUSIONS: MRI features of IIH are neither prognostic of visual nor headache outcome.

Retinal layer thinning as a biomarker of long-term disability progression in multiple sclerosis.

BACKGROUND: Peripapillary retinal nerve fibre layer and macular ganglion cell plus inner plexiform layer thinning are markers of neuroaxonal degeneration in multiple sclerosis. OBJECTIVE: We aimed to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning for prediction of long-term disability. METHODS: This is a 6-year prospective longitudinal study on 93 multiple sclerosis patients. Optical coherence tomography scans were performed at baseline, after 1, 2 and 6 years. Primary endpoint was disability progression after 6 years, defined as expanded disability status scale worsening and/or cognitive deterioration. Univariate and multivariate analysis was used to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer to predict the primary endpoint. RESULTS: A total of 57 (61.3%) patients had disability worsening, 40 (43.0%) expanded disability status scale worsening and 34 (36.6%) cognitive deterioration. Mean peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness were 93.0 and 75.2 µm, and mean annualised peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning rates over 6 years were 1.3 and 1.6 µm, respectively. Univariate and multivariate analysis revealed lower peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness and higher annualised thinning rates in patients with disability progression after 6 years. Effects were more pronounced for ganglion cell plus inner plexiform layer and expanded disability status scale worsening than for peripapillary retinal nerve fibre layer models and cognitive deterioration. CONCLUSION: Ganglion cell plus inner plexiform layer and peripapillary retinal nerve fibre layer measurements depict neurodegeneration and predict disability progression in multiple sclerosis.

Long-term outcome after COVID-19 infection in multiple sclerosis: a nation-wide multicenter matched-control study.

BACKGROUND: Long-term outcome after COVID-19 in patients with multiple sclerosis (pwMS) is scarcely studied and controlled data are lacking. OBJECTIVE: To compare long-term outcome after COVID-19 in pwMS to a matched control group of pwMS without COVID-19. METHODS: We included pwMS with PCR-confirmed diagnosis of COVID-19 and ≥6 months of follow-up available and, as a control group, pwMS matched 1:1 for age, sex, disability level and disease-modifying treatment type. RESULTS: Of 211 pwMS with COVID-19 (mean age 42.6 years [SD 12.2], 69% female, median EDSS 1.5 [range: 0-7.5], 16% antiCD20), 90.5% initially had a mild COVID-19 course. At follow-up, 70% had recovered completely 3 months (M3) after COVID-19, 83% after 6 months (M6) and 94% after 12 months (M12). Mild initial COVID-19 course was the only significant predictor of complete recovery (odds ratio [OR]: 10.5; p<0.001). Most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3: 13.7%, M6: 5.2%, M12: 1.7%) and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls, fatigue, hyposmia and dyspnea were significantly more frequent at M3 and still slightly at M6, while there was no difference at M12. PwMS with COVID-19 had neither a significantly increased risk for relapses (OR 1.1; p=0.70) nor disability worsening (OR 0.96; p=0.60). DISCUSSION: Long-term outcome of COVID-19 is favourable in a large majority of pwMS with only a small proportion of patients suffering from persistent symptoms usually resolving after 3-6 months. COVID-19 is not associated with increased risk of relapse or disability.