Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study.

BACKGROUND: It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course. METHODS: This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis. RESULTS: In total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015). CONCLUSIONS: In RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

Longevity of the humoral and cellular responses after SARS-CoV-2 booster vaccinations in immunocompromised patients.

We assessed the humoral and cellular immune responses after two booster mRNA vaccine administrations [BNT162b2 (Pfizer-BioNTech vaccine)] in cohorts of immunocompromised patients (n = 199) and healthy controls (HC) (n = 54). All patients living with HIV (PLWH) and chronic kidney disease (CKD) patients and almost all (98.2%) of the primary immunodeficiency (PID) patients had measurable antibodies 3 and 6 months after administration of the third and fourth vaccine dose, comparable to the HCs. In contrast, only 53.3% and 83.3% of the multiple sclerosis (MS) and rheumatologic patients, respectively, developed a humoral immune response. Cellular immune response was observed in all PLWH after administration of four vaccine doses. In addition, cellular immune response was positive in 89.6%, 97.8%, 73.3% and 96.9% of the PID, MS, rheumatologic and CKD patients, respectively. Unlike the other groups, only the MS patients had a significantly higher cellular immune response compared to the HC group. Administration of additional vaccine doses results in retained or increased humoral and cellular immune response in patients with acquired or inherited immune disorders.

Imaging of trochlear nerve schwannomas: a case series and systematic review of the literature.

Purpose Trochlear nerve schwannomas are rare tumors. So far, only 121 cases have been published. We present four new cases, discuss the imaging characteristics and summarize all previously published cases through a systematic review.Methods Four cases, all treated in AZ Sint-Jan Hospital Brugge-Oostende (Belgium), were collected, including their demographic, clinical and radiological data. All MR imaging was performed with the three-dimensional fluid-attenuated inversion recovery (3D-FLAIR), turbo spin echo T1 high-resolution (TSE T1 HR), three-dimensional balanced fast-field echo (3D b-FFE) and three-dimensional T1 black blood (3D T1 black blood) sequence. We compared our findings with the present literature through a systematic literature review in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.Results Screening with routine unenhanced 3D-FLAIR imaging could identify all schwannomas as hyperintense lesions on the course of the trochlear nerve. The use of 3D T1 black blood sequences was superior in depicting the lesions, while high-resolution 3D b-FFE images enabled us to visualize the anatomic boundaries of the lesions in detail. Most trochlear schwannomas are located in the ambient cistern, at or just below the free edge of the tentorium.Conclusion The majority of trochlear nerve schwannomas are located cisternal and display variable enhancement on contrast administration. 3D-FLAIR imaging is superior in detecting these lesions. Comparison with data collected from previous cases demonstrates the importance of early diagnosis and treatment. Generally, patients with trochlear nerve schwannomas have a good prognosis.

Rim lesions in MS at 3T: clinical correlation and possible radiological alternatives for daily practice at lower field strength.

BACKGROUND AND PURPOSE: Paramagnetic rim lesions (PRLs) have been described as an imaging feature specific to multiple sclerosis (MS) using high-field strength phase-sensitive MR imaging. These lesions are suggested to reflect chronic active inflammation associated with greater disease severity and a more rapid disability progression. The aim of our study is to investigate the relationship between PRLs, clinical parameters, other radiological findings and disease progression. MATERIAL AND METHODS: This cross-sectional study included MS patients treated with teriflunomide, fingolimod, natalizumab or ocrelizumab for at least 2 years. PRLs seen at 3T MRI were analysed and correlated with clinical data and radiological progression, defined as an increase of the T2/FLAIR-lesion load during therapy. In the search for alternatives for these PRLs, we defined two additional radiological markers: 'FLAIR-bullet lesions', and on post-contrast black-blood (BB) images, 'BB-bullet lesions'. RESULTS: We included 84 MS patients of whom 27 (32 %) had at least 1 PRL. PRLs were associated with radiological progression under therapy (p=0.039) and higher clinical disability scores, although only significant for 9-Hole Peg Test (p=0.023). Patients with FLAIR-bullet or BB-bullet lesions at 3T MRI had a higher chance of PRL (p<0.001) with a likelihood ratio of 13.2 for FLAIR-bullets and 12.6 for BB-bullet lesions, thanks to the high negative predictive value of respectively 83 % and 90 %. CONCLUSION: PRLs are associated with an increase of T2/FLAIR-lesion load under therapy and unfavourable clinical outcome. Our newly defined 'bullet lesions' are associated with PRLs and might be an interesting MRI marker for centres without access to high-field SWI images.

Smoldering lesions in MS: if you like it then you should put a rim on it.

PURPOSE: In multiple sclerosis (MS), chronic active/smoldering white matter lesions presenting with hypointense rims on susceptibility-weighted imaging (SWI) of the brain have been recognized as an important radiological feature. The aim of this work was to study the prevalence of paramagnetic rim lesions (RLs) in MS patients in a clinical setting and to assess differences in demographic and clinical variables regarding the presence of RLs. METHODS: All 3 T brain magnetic resonance (MR) studies performed in MS patients between July 2020 and January 2021 were reviewed. In all patients, RLs were assessed on three-dimensional (3D) SWI images and the T2 FLAIR lesion load volume was assessed. Demographic, laboratory (oligoclonal bands in CSF), and clinical data, including functional status with Expanded Disability Status Scale (EDSS), were retrieved from the clinical files. RESULTS: Of the 192 patients, 113 (59%) presented with at least 1 RL. In the RL-positive group, the mean RL count was 4.81 ranging from 1 to 37. There was no significant difference in the number of RLs between the different types of MS (p = 0.858). Regarding the presence of RLs, there were no significant differences based on gender (p = 0.083), disease duration (p = 0.520), treatment regime (p = 0.326), EDSS score (p = 0.103), and the associated T2 FLAIR lesion load volume. CONCLUSION: SWI RLs were frequently detected in our cohort regardless of the MS type, T2 FLAIR lesion load volume, demographic features, disease duration, or clinical score. Our results suggest that RLs are not associated with more severe forms of the disease. Today, RLs can be seen on 3 T 3D SWI, although this is not a clinical standard sequence yet. Therefore, it should be considered an additional helpful MR sequence in the diagnostic workup of MS, although more studies are warranted to establish the role of RLs as prognostic markers.

Alemtuzumab in multiple sclerosis: A retrospective analysis of occult hemorrhagic magnetic resonance imaging lesions and risk factors.

BACKGROUND AND PURPOSE: Alemtuzumab, a monoclonal CD52 antibody, is a high-efficacy disease-modifying-therapy in relapsing-remitting multiple sclerosis (RRMS). Recently, intracerebral hemorrhage (ICH) was reported as a possible treatment-related adverse event. Arterial hypertension during infusion was suggested as a potential cause, although platelet or endothelial dysfunction may also contribute. This study aimed to screen for occult hemorrhagic cerebral lesions after alemtuzumab treatment and to further elucidate risk factors. METHODS: We included 30 RRMS patients who received alemtuzumab treatment at Ghent University Hospital or Sint-Jan Bruges Hospital. Retrospective data concerning vital signs, adverse effects and thrombocyte levels during treatment were collected. The occurrence of occult intracranial hemorrhagic lesions was assessed by magnetic resonance imaging with susceptibility-weighted imaging (SWI). RESULTS: The mean (standard deviation [SD]) systolic blood pressure (SBP) during the morning, afternoon and evening was 120 (3.38) mmHg during first administration and 114 (4.40) mmHg during second administration (N = 13). There was no significant increase in SBP when comparing morning, afternoon and evening per day, nor was there a significant difference in daily mean SBP between consecutive administration days. Thrombocyte count during treatment cycles ranged between 107 × 109 /L and 398 × 109 /L, with a mean (SD) absolute reduction of 59.3 × 109 /L (50.65) or a mean (SD) relative reduction of 25.0 (12.84)% (N = 20). No patient had ICH, nor did SWI show any cerebral microbleeds or other hemorrhagic lesions post-treatment (N = 23). CONCLUSIONS: In our patient population, alemtuzumab treatment was not associated with arterial hypertension, ICH or occult microbleeds. Possible differences in administration regimen (ambulatory vs. in-hospital setting) and patient population (cardiovascular risk) might explain an increased risk in different populations.

Single MRI-Based Volumetric Assessment in Clinical Practice Is Associated With MS-Related Disability.

BACKGROUND: The added value of brain volume measurements in the clinical practice of multiple sclerosis (MS) has been questioned. PURPOSE: To investigate the contribution of volume measures obtained with magnetic resonance scans performed as part of regular care to predict measures of cognitive and physical MS disability in a real-world setting. STUDY TYPE: Retrospective. SUBJECTS: In all, 470 adults with diagnosed MS. FIELD STRENGTH/SEQUENCE: 3D fluid attenuation inversion recovery (FLAIR) and 3D T1 -weighted MR images at 3.0T MR. ASSESSMENT: Lesion and brain volume were measured by an automated method, MSmetrix, developed by icometrix. STATISTICAL TESTS: We used stepwise linear regression models to assess the added value of a single volumetric assessment in predicting Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Brain volumes categorized into quartiles were used as predictive variables in a time-to-event analysis and Cox proportional hazard regression with time to worsening from baseline as outcome measures. RESULTS: Brain and lesion volume in relapsing onset MS strongly contributed to the best models, with a substantial role for age in the EDSS model and a modest role for education in the SDMT model. Adding MR volumetric information increased the explained variance from 17% to 28% in the best model for EDSS and from 9% to 25% in the best model for SDMT. A significantly reduced hazard (P < 0.05) of SDMT worsening was found in the highest normalized brain volume quartiles (1375-1608 ml), compared with the lowest quartile (1201-1374 ml) in the total study population. DATA CONCLUSION: Our findings indicate that a single brain volumetric assessment contributes to the prediction of MS-related disability, with distinct patterns for EDSS as a measure of physical disability, and SDMT as a measure of cognitive disability. A threshold effect for the lowest brain volumes with regard to SDMT worsening over time was found. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1312-1321.

Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial.

BACKGROUND: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). OBJECTIVE: To determine whether fluoxetine slows accumulation of disability in progressive MS. METHODS: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). RESULTS: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test (p = 0.258) and Cox regression analysis (p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. CONCLUSION: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.

Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.

Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein. The jugular vein/peripheral vein ratio was 1.4 in patients with MS vs. 1.1 in control subjects, suggesting that, in MS, ET-1 is released from the brain to the cerebral circulation. Next, we performed ET-1 immunohistochemistry on postmortem white matter brain samples and found that the likely source of ET-1 release are reactive astrocytes in MS plaques. We then used arterial spin-labeling MRI to noninvasively measure CBF and assess the effect of the administration of the ET-1 antagonist bosentan. CBF was significantly lower in patients with MS than in control subjects and increased to control values after bosentan administration. These data demonstrate that reduced CBF in MS is mediated by ET-1, which is likely released in the cerebral circulation from reactive astrocytes in plaques. Restoring CBF by interfering with the ET-1 system warrants further investigation as a potential new therapeutic target for MS.

Autonomic function in migraine patients: ictal and interictal pupillometry.

OBJECTIVE AND BACKGROUND: Pupillometric investigations into migraine have suggested that an autonomic disturbance is part of the pathogenesis of that condition. This observation is controversial, however, which may reflect that the putative sympathetic hypofunction is either subtle or transient. In this study, we assessed the sympathetic function of migraine patients and controls during both a symptom-free phase and a migraine attack, and challenged patients with apraclonidine to reveal small changes in autonomic function. METHODS: Infrared pupillometry was used to measure pupillometric parameters in 37 controls and 46 migraine patients in the interictal phase of disease. Fifteen migraine patients were also studied during a migraine attack. In addition, 26 controls and 18 migraine patients were tested interictally both with and without apraclonidine. Of these 18 migraine patients, seven were also tested with and without apraclonidine during a migraine attack. RESULTS: We found no significant differences between migraine patients and controls in the interictal phase. Additionally, no differences in pupil parameters were detected during the migraine attack. However, after administration of apraclonidine, migraine patients had a longer latency of the light reflex compared with controls. This increase in latency was more pronounced ictally (oculus dexter: P = .046, oculus sinister: P = .023) than interictally (oculus dexter: P = .075, oculus sinister: P = .021). CONCLUSIONS: We conclude that there is evidence for a subtle pupillary sympathetic hypofunction in migraine patients, observed as a prolonged latency to light reflex, which is revealed after the administration of apraclonidine.

Inter-assay diagnostic accuracy of cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis.

Background: Cerebrospinal fluid (CSF) kappa free light chain (κFLC) measures gained increasing interest as diagnostic markers in multiple sclerosis (MS). However, the lack of studies comparing assay-dependent diagnostic cutoff values hinders their use in clinical practice. Additionally, the optimal κFLC parameter for identifying MS remains a subject of ongoing debate. Objectives: The aim of this study was to compare same-sample diagnostic accuracies of the κFLC index, κIgG index, CSF κFLC/IgG ratio, and isolated CSF κFLC (iCSF-κFLC) between two reference centers using different methods. Methods: Paired serum and CSF samples were analyzed for κFLC and albumin concentrations by Freelite®-Optilite (Sint-Jan Bruges hospital) and N Latex®-BNII (Ghent University hospital). Diagnostic performance to differentiate MS from controls was assessed using ROC curve analysis. Results: A total of 263 participants were included (MS, n = 80). Optimal diagnostic cutoff values for the κFLC index (Freelite®-Optilite: 7.7; N Latex®-BNII: 4.71), κIgG index (Freelite®-Optilite: 14.15, N Latex®-BNII: 12.19), and CSF κFLC/IgG ratio (Freelite®-Optilite: 2.27; N Latex®-BNII: 1.44) differed between the two methods. Sensitivities related to optimal cutoff values were 89.9% (Freelite®-Optilite) versus 94.6% (N Latex®-BNII) for the κFLC index, 91% (Freelite®-Optilite) versus 92.2% (N Latex®-BNII) for the κIgG index, and 81.3% (Freelite®-Optilite) versus 91.4% (N Latex®-BNII) for the CSF κFLC/IgG ratio. However, for iCSF-κFLC, optimal diagnostic cutoff values (0.36 mg/L) and related specificities (81.8%) were identical with a related diagnostic sensitivity of 89.9% for Freelite®-Optilite and 90.5% for N Latex®-BNII. The diagnostic performance of the κFLC index [area under the curve (AUC) Freelite®-Optilite: 0.924; N Latex®-BNII: 0.962] and κIgG index (AUC Freelite®-Optilite: 0.929; N Latex®-BNII: 0.961) was superior compared to CSF oligoclonal bands (AUC: 0.898, sensitivity: 83.8%, specificity: 95.9%). Conclusions: The κFLC index and the κIgG index seem to be excellent markers for identifying MS, irrespective of the method used for κFLC quantification. Based on the AUC, they appear to be the measures of choice. For all measures, optimal cutoff values differed between methods except for iCSF-κFLC. iCSF-κFLC might therefore serve as a method-independent, more cost-efficient, initial screening measure for MS. These findings are particularly relevant for clinical practice given the potential future implementation of intrathecal κFLC synthesis in MS diagnostic criteria and for future multicentre studies pooling data on κFLC measures.

Multiple Sclerosis Multidisciplinary Care: A National Survey and Lessons for the Global Community.

BACKGROUND: Access to, standardization and reimbursement of multidisciplinary care for people with MS (PwMS) is lacking in many countries. Therefore, this study aims to describe the current multidisciplinary care for people with MS (PwMS) in Belgium and identify benefits, needs and future perspectives METHODS: A survey for PwMS questioned various aspects of MS and viewpoints on care. For MS nurses (MSN) and neurologists, employment, education, job-content, care organization and perspectives were inquired. Descriptive and univariate statistics were performed RESULTS: The PwMS survey comprised 916 respondents with a mean age of 46±12.7 years and 75,4 % of the respondents being female. The majority of the participants had relapsing remitting MS (60.8 %) and the mean patient determined disease steps (PDDS) was 2.0 (IQR=3). 65.3 % and 60.4 % of the PwMS reported having access to a multidisciplinary team (MDT) or MSN. Access to an MSN was associated with more frequent disease modifying treatment (p=.015), spasticity (p=.042) and gait treatment (p=.035), but also more physiotherapy (p=.004), driver's license adjustment (p<.001) and a higher employment rate (p=.004). MDT access was associated with more frequent symptomatic bladder treatment (p=.047), higher physiotherapy rate (p<.001), higher work- (p=.002), insurance- (p<.001) and home support measures (p=.019). PwMS without an available MDT more often indicated that MS care needs improvement (p<.001). MSN's (n = 22) were mainly funded through various budgets, including hospital and neurology practice budgets. Finally, 69 % and 75 % neurologists (n = 62) working without an MSN or MDT stated a need of such support and 61 % agreed that MDT's should be organized at hospital-network level CONCLUSION: MDT and MSN availability may enhance medical and socio-economic support for PwMS. Guidelines, alignment and reimbursement are needed.

A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial.

Introduction: Despite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive multiple sclerosis (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers of disability progression that are insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing of metformin for treatment of PMS. The objective of this clinical trial is to evaluate whether metformin, as add-on treatment, is superior to placebo in delaying disease progression in patients with non-active PMS. Methods and analysis: MACSiMiSE-BRAIN is a multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled clinical trial, conducted at five sites in Belgium. Enrollment of 120 patients with non-active PMS is planned. Each participant will undergo a screening visit with assessment of baseline magnetic resonance imaging (MRI), clinical tests, questionnaires, and a safety laboratory assessment. Following randomization, participants will be assigned to either the treatment (metformin) or placebo group. Subsequently, they will undergo a 96-week follow-up period. The primary outcome is change in walking speed, as measured by the Timed 25-Foot Walk Test, from baseline to 96 weeks. Secondary outcome measures include change in neurological disability (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) and hand function (9-Hole Peg test). Annual brain MRI will be performed to assess evolution in brain volumetry and diffusion metrics. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score will be additionally evaluated as an exploratory outcome. Other exploratory outcomes will consist of paramagnetic rim lesions, the 2-minute walking test and health economic analyses as well as both patient- and caregiver-reported outcomes like the EQ-5D-5L, the Multiple Sclerosis Impact Scale and the Caregiver Strain Index. Ethics and dissemination: Clinical trial authorization from regulatory agencies [Ethical Committee and Federal Agency for Medicines and Health Products (FAMHP)] was obtained after submission to the centralized European Clinical Trial Information System. The results of this clinical trial will be disseminated at scientific conferences, in peer-reviewed publications, to patient associations and the general public. Trial registration: ClinicalTrials.gov Identifier: NCT05893225, EUCT number: 2023-503190-38-00.

Prehospital unassisted assessment of stroke severity using telemedicine: a feasibility study.

BACKGROUND AND PURPOSE: We evaluated the feasibility and the reliability of remote stroke severity quantification in the prehospital setting using the Unassisted TeleStroke Scale (UTSS) via a telestroke ambulance system and a fourth-generation mobile network. METHODS: The technical feasibility and the reliability of the UTSS were studied in healthy volunteers mimicking 41 stroke syndromes during ambulance transportation. RESULTS: Except for 1 issue, high-quality telestroke assessment was feasible in all scenarios. The mean examination time for the UTSS was 3.1 minutes (SD, 0.4). The UTSS showed excellent intrarater and interrater variability (ρ=0.98 and 0.97; P<0.001), as well as excellent internal consistency and rater agreement. Adequate concurrent validity can be derived from the strong correlation between the UTSS and the National Institutes of Health Stroke Scale (ρ=0.90; P<0.001). CONCLUSIONS: Remote assessment of stroke severity in fast-moving ambulances using a system dedicated to prehospital telemedicine, 4G technology, and the UTSS is feasible and reliable.

Cerebral white matter blood flow and energy metabolism in multiple sclerosis.

BACKGROUND: Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown. OBJECTIVE: The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism. METHODS: Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using (1)H-MR spectroscopy and PCr/ß-ATP ratios using (31)P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/ß-ATP ratios. RESULTS: Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/ß-ATP was increased. We found no correlations between CBF and PCr/ß-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68). CONCLUSIONS: Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.

Radial diffusivity reflects general decline rather than specific cognitive deterioration in multiple sclerosis.

Advanced structural brain imaging techniques, such as diffusion tensor imaging (DTI), have been used to study the relationship between DTI-parameters and cognitive scores in multiple sclerosis (MS). In this study, we assessed cognitive function in 61 individuals with MS and a control group of 35 healthy individuals with the Symbol Digit Modalities Test, the California Verbal Learning Test-II, the Brief Visuospatial Memory Test-Revised, the Controlled Oral Word Association Test, and Stroop-test. We also acquired diffusion-weighted images (b = 1000; 32 directions), which were processed to obtain the following DTI scalars: fractional anisotropy, mean, axial, and radial diffusivity. The relation between DTI scalars and cognitive parameters was assessed through permutations. Although fractional anisotropy and axial diffusivity did not correlate with any of the cognitive tests, mean and radial diffusivity were negatively correlated with all of these tests. However, this effect was not specific to any specific white matter tract or cognitive test and demonstrated a general effect with only low to moderate individual voxel-based correlations of <0.6. Similarly, lesion and white matter volume show a general effect with medium to high voxel-based correlations of 0.5-0.8. In conclusion, radial diffusivity is strongly related to cognitive impairment in MS. However, the strong associations of radial diffusivity with both cognition and whole brain lesion volume suggest that it is a surrogate marker for general decline in MS, rather than a marker for specific cognitive functions.

Evaluation of Humoral and Cellular Responses in SARS-CoV-2 mRNA Vaccinated Immunocompromised Patients.

Background: Immunocompromised patients are at increased risk of severe COVID-19 and impaired vaccine response. In this observational prospective study, we evaluated immunogenicity of the BNT162b2 mRNA vaccine in cohorts of primary or secondary immunocompromised patients. Methods: Five clinical groups of immunocompromised patients [primary immunodeficiency (PID) (n=57), people living with HIV (PLWH) (n=27), secondary immunocompromised patients with a broad variety of underlying rheumatologic (n=23) and homogeneous (multiple sclerosis) neurologic (n=53) conditions and chronic kidney disease (CKD) (n=39)] as well as a healthy control group (n=54) were included. Systemic humoral and cellular immune responses were evaluated by determination of anti-SARS-CoV-2 Spike antibodies using a TrimericS IgG assay (Diasorin) and through quantification of interferon gamma release in response to SARS-CoV-2 antigen with QuantiFERON SARS-CoV-2 assay (Qiagen), respectively. Responses were measured at pre-defined time-points after complete vaccination. Results: All healthy controls, PLWH and CKD-patients had detectable antibodies 10 to 14 days (T2) and 3 months (T3) after administration of the second vaccination. In contrast, only 94.5% of the PID, 50.0% of the rheumatologic and 48.0% of neurologic patients developed antibodies at T2 and only 89.1% of the PID, 52.4% of the rheumatologic and 50.0% of neurologic patients developed antibodies at T3. At T3 no significant differences in cellular response between the healthy control group and the PLWH and CKD groups were found, while proportions of reactive subjects were lower in PID and rheumatologic patients and higher in neurologic patients. Humoral and cellular immune responses significantly correlated in the healthy control, PID, PLWH groups for all 3 antigens. Conclusion: Patients with acquired or inherited immune disorders may show variable immune responses to vaccination with the BNT162b2 mRNA vaccine against SARS-CoV-2. Whether humoral, cellular or both immune responses are delayed depends on the patient group, therapy and individual risk factors. These data may guide the counselling of patients with immune disorders regarding vaccination of SARS-CoV-2.

Apraclonidine and my pupil.

PURPOSE: Used in the diagnosis of Horner's syndrome, apraclonidine 1% dilatates the involved eye due to denervation supersensitivity. Recent literature suggests that in healthy volunteers, apraclonidine provokes a mild miotic effect. Since the comparison of both the pathologic and the non-pathologic eye is important, we wanted to further investigate the effect of apraclonidine on the healthy eye. By measuring the effect on the pupil intermittently over a few hours, we tried to determine the best moment for evaluation after instillation with apraclonidine. Therefore, the effect of apraclonidine on pupillary parameters was investigated in 14 healthy volunteers. METHODS: Infrared pupillography was used to measure the scotopic pupil diameter and the dynamic pupil responses to light. The first measurements were performed prior to instillation of apraclonidine. Measurements were retaken 30, 60, 90, 120, 180, 240, 300 and 360 min after random instillation of one eye with one drop of 1% apraclonidine. RESULTS: The anisocoria after dark adaptation and at minimum pupil diameter differed significantly for the measurements obtained 30 and 60 min after instillation with apraclonidine. The eye with apraclonidine drops showed relative miosis and an increased amplitude of constriction to light. No significant influence was found on the latency, the constriction velocity and redilation velocity. CONCLUSIONS: Instillation of apraclonidine 1% in healthy subjects causes relative miosis, which is most pronounced after 30-60 min. The amplitude of constriction to light also differs significantly. The relative miotic effect of apraclonidine could be explained by the α-2 receptor agonistic effect which is more pronounced than the α-1 agonistic effect in healthy subjects. In patients with Horner's syndrome, the α-1 agonistic effect will dominate because of the supersensitivity of the α-1 receptors, resulting in relative mydriasis. These findings stress the necessity to instill the unaffected eye in diagnosing a suspected Horner's pupil.

Signal quality as Achilles' heel of graph theory in functional magnetic resonance imaging in multiple sclerosis.

Graph-theoretical analysis is a novel tool to understand the organisation of the brain.We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.