Ocrelizumab in people with primary progressive multiple sclerosis: A real-world multicentric study.

BACKGROUND: Ocrelizumab is the only disease-modifying therapy (DMT) approved for the treatment of people with primary progressive multiple sclerosis (pwPPMS). OBJECTIVES: To provide real-world evidence of ocrelizumab effectiveness and safety in pwPPMS in Croatian MS centers. METHODS: A retrospective observational multi-center study of pwPPMS who were started on ocrelizumab in 7 MS centers in Croatia. RESULTS: We identified 230 pwPPMS of whom 176 fulfilled the inclusion criteria. The median follow-up of the cohort was 2.73 (0.51-5.77) years. During the follow-up, 50 (28.4%) pwPPMS experienced confirmed disability worsening (CDW) and 19 (10.8%) stopped treatment with ocrelizumab. Baseline EDSS >5 was a statistically significant positive predictor for the development of CDW and/or stop of the treatment due to any cause (OR 2.482, 95% C.I. 1.192-5.166, p = 0.015). However, there was no significant difference in the development of CDW and/or stop of the treatment due to any cause if stratifying the patients based on active PPMS, age at treatment start (≤55 years vs >55 years), disease duration at treatment start (≤10 years vs >10 years), or EDSS at treatment start (≤5.0 vs >5.0). During the follow-up, 26 (14.8%) pwPPMS experienced infusion reactions, 64 (36.4%) had an infection and 4 (2.3%) developed a tumor. The percentage of pwPPMS with low levels of IgG was persistently above 10% and with low levels of IgM was persistently above 20% after cycle 4. CONCLUSION: Our real-world data support the use of ocrelizumab in a much broader pwPPMS population than in the original randomized controlled trial.

Treated and Untreated Primary Progressive Multiple Sclerosis: Walkthrough Immunological Changes of Monocytes and T Regulatory Cells.

The objective of this study was to investigate regulatory T cells (Tregs) and monocytes; specifically, the expression of CTLA-4 (CD152) and FOXP3+ in CD4+CD25+ Tregs and the expression of CD40+ and CD192+ monocyte subpopulations in subjects with primary progressive multiple sclerosis (PPMS). Immunological analysis was conducted on peripheral blood samples collected from the 28 PPMS subjects (15 treated with ocrelizumab and 13 untreated PPMS subjects) and 10 healthy control subjects (HCs). The blood samples were incubated with antihuman CD14, CD16, CD40, and CD192 antibodies for monocytes and antihuman CD4, CD25, FOXP3, and CTLA-4 antibodies for lymphocytes. The study results showed that in comparison to HCs both ocrelizumab treated (N = 15) and untreated (N = 13) PPMS subjects had significantly increased percentages of CTLA-4+ and FOXP3+ in CD4+CD25+ Tregs. Further, ocrelizumab treated PPMS subjects, compared to the untreated ones, had significantly decreased percentages of CD192+ and CD40+ nonclassical monocytes. Increased percentages of CTLA-4+ and FOXP3+ in CD4+CD25+ Tregs in both ocrelizumab treated and untreated PPMS subjects indicates the suppressive (inhibitory) role of Tregs in abnormal immune responses in PPMS subjects. Decreased percentages of CD40+ and CD192+ non-classical CD14+CD16++ monocytes for treated compared to untreated PPMS subjects suggests a possible role for ocrelizumab in dampening CNS inflammation.

Transcranial Magnetic Stimulation Measures, Pyramidal Score on Expanded Disability Status Scale and Magnetic Resonance Imaging of Corticospinal Tract in Multiple Sclerosis.

Probing the cortic ospinal tract integrity by transcranial magnetic stimulation (TMS) could help to understand the neurophysiological correlations of multiple sclerosis (MS) symptoms. Therefore, the study objective was, first, to investigate TMS measures (resting motor threshold-RMT, motor evoked potential (MEP) latency, and amplitude) of corticospinal tract integrity in people with relapsing-remitting MS (pwMS). Then, the study examined the conformity of TMS measures with clinical disease-related (Expanded Disability Status Scale-EDSS) and magnetic resonance imaging (MRI) results (lesion count) in pwMS. The e-field navigated TMS, MRI, and EDSS data were collected in 23 pwMS and compared to non-clinical samples. The results show that pwMS differed from non-clinical samples in MEP latency for upper and lower extremity muscles. Also, pwMS with altered MEP latency (prolonged or absent MEP response) had higher EDSS, general and pyramidal, functional scores than pwMS with normal MEP latency finding. Furthermore, the RMT intensity for lower extremity muscles was predictive of EDSS functional pyramidal scores. TMS/MEP latency findings classified pwMS as the same as EDSS functional pyramidal scores in 70-83% of cases and were similar to the MRI results, corresponding to EDSS functional pyramidal scores in 57-65% of cases. PwMS with altered MEP latency differed from pwMS with normal MEP latency in the total number of lesions in the brain corticospinal and cervical corticospinal tract. The study provides preliminary results on the correspondence of MRI and TMS corticospinal tract evaluation results with EDSS functional pyramidal score results in MS.

Expression of CD40 and CD192 in Classical Monocytes in Multiple Sclerosis Patients Assessed with Transcranial Magnetic Stimulation.

Expression of CD40 and CD192 markers in different monocyte subpopulations has been reported to be altered in people with MS (pwMS). Also, functional connectivity of the corticospinal motor system pathway alterations has been proved by transcranial magnetic stimulation (TMS). The study objective was to investigate the expression of CD40 and CD192 in classical (CD14++CD16-), intermediate CD14++CD16+ and non-classical (CD14+CD16++) blood monocyte subpopulations in pwMS, undergoing neurophysiological TMS assessment of the corticospinal tract integrity by recording motor-evoked potentials (MEPs). Radiological examination on lesion detection with MRI was performed for 23 patients with relapsing-remitting MS treated with teriflunomide. Then, immunological analysis was conducted on peripheral blood samples collected from the patients and 10 healthy controls (HC). The blood samples were incubated with anti-human CD14, CD16, CD40 and CD192 antibodies. Next, pwMS underwent neurological testing of functional disability (EDSS) and TMS assessment with recording MEPs from upper and lower extremity muscles. The results show that in comparison to HC subjects, both pwMS with normal and altered MEP findings (prolonged MEP latency or absent MEP response) had significantly decreased surface receptor expression measured (MFIs) of CD192 and increased CD40 MFI in classical monocytes, and significantly increased percentages of classical and total monocytes positive for CD40. Knowing CD40's pro-inflammatory action, and CD192 as a molecule that enables the passing of monocytes into the brain, decreased CD192 in classical monocytes could represent a beneficial anti-inflammatory parameter.

Confirmation of CD19+ B-Lymphocyte Depletion Prior to Intake of the Second Dose of Ocrelizumab in Multiple Sclerosis Patients.

The aim of the retrospective study was to compare the immunophenotyping of T-lymphocytes, B-lymphocytes, and natural killer cells before the administration of the first and the second dose of ocrelizumab in 22 patients with multiple sclerosis in a three-year period (2019-2021) at the Department of Neurology of the University Hospital of Split. The values of cell immunophenotyping and protein electrophoresis, as well as laboratory parameters, were investigated. There was no significant decrease in serum albumin and globulins before the second dose of ocrelizumab (p > 0,05). A decrease in the number of T-lymphocytes before administration of the second dose of ocrelizumab was observed, but without statistical significance (p = 0.274). Significant depletion occurred in median CD19+ B-lymphocytes (p < 0.001) before the intake of the second dose of ocrelizumab confirming the primary action of ocrelizumab on the B cell lineage.

Assessment of Motor Evoked Potentials in Multiple Sclerosis.

Transcranial magnetic stimulation (TMS) is a noninvasive technique mainly used for the assessment of corticospinal tract integrity and excitability of the primary motor cortices. Motor evoked potentials (MEPs) play a pivotal role in TMS studies. TMS clinical guidelines, concerning the use and interpretation of MEPs in diagnosing and monitoring corticospinal tract integrity in people with multiple sclerosis (pwMS), were established almost ten years ago and refer mainly to the use of TMS implementation; this comprises the magnetic stimulator connected to a standard EMG unit, with the positioning of the coil performed by using the external landmarks on the head. The aim of the present work was to conduct a narrative literature review on the MEP assessment and outcome measures in clinical and research settings, assessed by TMS Methodological characteristics of different TMS system implementations (TMS without navigation, line-navigated TMS and e-field-navigated TMS); these were discussed in the context of mapping the corticospinal tract integrity in MS. An MEP assessment of two case reports, by using an e-field-navigated TMS, was presented; the results of the correspondence between the e-field-navigated TMS with MRI, and the EDSS classifications were presented. Practical and technical guiding principles for the improvement of TMS studies in MEP assessment for MS are discussed, suggesting the use of e-field TMS assessment in the sense that it can improve the accuracy of corticospinal tract integrity testing by providing a more objective correspondence of the neurophysiological (e-field-navigated TMS) and clinical (Expanded Disability Status Scale-EDSS) classifications.

Possible influence of styloid process length on isolated vertigo of unknown aetiology.

OBJECTIVE: Eagle syndrome or styloid process syndrome is a clinical condition of complex aetiology. Since, as a consequence of vascular compression,due to the length of the styloid process and its nearness to the internal carotid artery,it can lead to vertigo. Vertigo may be the only symptom of stylocarotid syndrome and it is extremely challenging diagnose.To the best of our knowledge, this is the first study that measures the lengths of styloid process on the Croatian population's,and possible influence of styloid process length on isolated vertigo of unknown aetiology. METHODS: This study included 829 subjects who were divided into two groups.The first group was the control group, consisting of 800 subjects.The second group, study group, consisted of 29 subjects who suffered from the vertigo of unknown aetiology. RESULTS: The statistically significant difference between the study and the control group was observed in the length of the styloid process, and in the closest distance of the styloid process from the carotid artery. CONCLUSIONS: The prolonged styloid process and its close association with the internal carotid artery may affect vertigo of unknown aetiology and should be clinically and radiographically investigated in cases of unexplained vertigo as an isolated and only symptom within stylocarotid syndrome.

Symptom-Level Disability Status Assessed with an Electronic Unsupervised Patient-Reported Expanded Disability Status Scale (ePR-EDSS) in Multiple Sclerosis Patients-The Example of Croatia.

The present study aimed to apply an electronic, unsupervised patient-reported Expanded Disability Status Scale (ePR-EDSS) to investigate disability severity in people with multiple sclerosis (pwMS) as a case study in Croatia in 2021, including demographic and comorbidity characteristics and multiple sclerosis (MS) disease-related factors. The cross-sectional study was conducted as an online survey from 4 October 2021 to 31 December 2021. Symptom-level disability status was assessed with ePR-EDSS for MS capturing MS-related disability across the spectrum of severity.The study enrolled 147 pwMS patients, of which 84% were women. The mean age ± standard deviation in the sample was 41.1 ± 11.3, and the mean disease duration was 8.5 ± 7.4 years, with a median EDSS score of 3.0 (range, 0−8). The distribution of the participants according to clinical forms of MS was as follows: 71% had relapsing-remitting MS, 13% had primary progressive MS, 4% had secondary progressive PMS, and 12% did not provide information on their MS type. Twenty-nine point two percent (29.2%) of the participants had comorbidities in addition to MS. EDSS scores indicate significant differences with regard to age (t = −3.51, p < 0.001), gender (χ2 = 8.04, p < 0.01), and immunomodulatory drug use (χ2 = 5.89, p < 0.05). An ePR-EDSS analysis of disability symptoms showed a significant difference in symptoms with regard to strength, sensation, coordination, vision, fatigue, mobility, and overall wellness among MS types. Participants with PPMS and SPMS were older on average, had higher EDSS, and had more pronounced symptoms of disability measured with ePR-EDSS compared to those with RRMS. Application of ePR-EDSS shows it to be a reliable eHealth tool for clinical assessment of pwMS disability status, and future studies should correlate it with standard self-report scales capturing MS symptoms such as fatigue, depression, anxiety, and stress.

Psychometric Properties of the Pittsburgh Sleep Quality Index (PSQI) in Patients with Multiple Sclerosis: Factor Structure, Reliability, Correlates, and Discrimination.

Sleep disturbances and poor sleep are a common complaint in the population with multiple sclerosis (MS) disease. The most commonly reported scale is the Pittsburgh Sleep Quality Index (PSQI), measuring seven components of sleep quality. Yet, till today, the PSQI instrument has not been validated in people with multiple sclerosis (pwMS). The objective of our study was to add precision in sleep quality assessment by investigating the psychometric properties of PSQI (factor structure, reliability, validity based on relations with other variables, cut-off scores) in pwMS. The cross-sectional study included data on a total of 87 patients with MS and 216 control subjects. Demographic information, education level, and MS-related variables were ascertained. Psychometric properties were examined by estimating the validity, including factor structure, metric invariance, and relations with other MS- and non-MS-related variables, reliability, and discrimination ability of the PSQI. The Croatian version of the PSQI had a two-factor structure which demonstrated loading and partial intercept invariance between pwMS and the control group. The global score and both subscales had high internal consistencies (McDonald's omega and Cronbach's alpha coefficients) in pwMS and showed expected relations with demographic and MS-related variables. PwMS differed significantly in the PSQI global score from the control groups, although receiver operating characteristics (ROC) curve analysis did not indicate a clear cut-off point. The PSQI is a reliable and valid scale and can be applied in clinical settings for assessing sleep quality in pwMS.

The significance of immunohistochemical expression of merlin, Ki-67, and p53 in meningiomas.

Meningiomas are one of the most common CNS tumors whose appearance is closely linked to NF2 gene product merlin. Tumor markers Ki-67 and p53 play established role in tumor progression which should be analyzed in close association with merlin expression. The aim of this study was to investigate the immunohistochemical expression of merlin in meningiomas, correlation with Ki-67 and p53, and to determine the association of these results with histologic grade and subtype. The histologic sections of 170 patients with totally resected meningiomas, between January 2000 and December 2010, were classified according to WHO, immunohistochemically stained for Ki-67, p53, and merlin, and analyzed using light microscope. Ki-67 median was 5.6 times higher in group of patients with negative merlin than in those with positive merlin (P=0.05). Statistically significant correlation of merlin with p53 was found (P<0.001). Merlin expression between 2 combined groups (meningothelial/secretory and fibroblastic/transitional) was statistically significant (P=0.002). By comparing merlin expression and p53 levels, statistically significant difference was found (P=0.017). In the group with positive merlin and negative p53 as well as positive merlin and low p53, meningothelial/secretory subtypes of meningiomas were more common. In combination of negative merlin and negative p53 as well as negative merlin and high p53, there were more meningiomas of fibroblastic/transitional subtype. There was no statistically significant correlation between merlin and tumor grade (P=0.420). There is undeniable influence of merlin on the development and the proliferative ability of meningioma subtypes. Significant role of p53 pathway was confirmed.

P300 wave changes in patients with multiple sclerosis.

INTRODUCTION: In patients with multiple sclerosis among other symptoms occur cognitive dysfunctions, which can be shown by P300 wave changes. GOAL: The aim of this study was to demonstrate that patients with multiple sclerosis have reduced amplitude and prolonged latency, longer than 300 ± 10 ms. METHODS: The study included group of patients with multiple sclerosis and control group. After reviewing the medical records both groups of 14 participants were subjected to the same testing procedures auditory cognitive potentials (P300). RESULTS: We have shown that patients with multiple sclerosis don't have prolonged P300 target stimulus latency, but they have a longer P300 frequent stimulus latency for 18 ms. From 14 patients seven had a pathological P300 target stimulus amplitude, and even 12 patient had pathological P300 frequent stimulus amplitude. CONCLUSION: People with multiple sclerosis have altered P300 which indicates the presence of cognitive dysfunction in these patients.

Use of cerebrospinal fluid biomarker analysis for improving Alzheimer's disease diagnosis in a non-specialized setting.

Low levels of amyloid-beta42 (Abeta42) and high total-tau (t-tau) or phosphorylated-tau (p181-tau) levels in cerebrospinal fluid (CSF) were shown to be characteristic for Alzheimer's disease (AD) patients and for mildly cognitively impaired (MCI) or non-demented individuals who will progress to AD. The goal of this study was to evaluate the benefit of CSF biomarker testing in a setting with no specialized dementia centers, in order to improve the accuracy of AD diagnosis and to identify individuals with incipient AD. Using ELISA assay we analyzed CSF Abeta42, t-tau and p181-tau levels among clinically diagnosed non-demented individuals, AD patients and individuals with uncertain dementia (n=36). CSF cut-off values of low Abeta42 (less than or equal to 530 pg/mL) and high t-tau (less than or equal to 350 pg/mL) or p181-tau (less than or equal to 52 pg/mL) were used to identify individuals with AD/MCI-CSF profile, regardless of clinical diagnosis. APOE genotyping was performed using PCR-RFLP method. In accord with previous studies we detected significantly decreased levels of CSF Abeta42 and increased tau and p181-tau levels in clinically diagnosed AD group vs. non-demented controls. CSF profiling identified individuals with a typical AD/MCI-CSF pattern in clinically referred non-demented group (9 percent) and among patients with uncertain dementia (41.7 percent). APOE epsilon4-allele was associated with the CSF biomarker changes typical for AD. This study shows that in a non-specialized setting CSF biomarker testing may be used as a screening tool for improving the accuracy of AD diagnosis and for predicting individuals with incipient Alzheimer's disease who need to receive further clinical follow-up.

Prevalence of migraine, probable migraine and tension-type headache in the Croatian population.

BACKGROUND/AIM: Population-based epidemiological studies about headaches, especially migraine, have been carried out in many countries. The aim of this study was to assess the 1-year prevalence of migraine, probable migraine and tension-type headache (TTH) in the Croatian population. METHODS: The design of the study was a cross-sectional survey of an adult population sample using a self-completed questionnaire. RESULTS: The 1-year crude prevalence of migraine without and with aura in this study was 7.5%, of probable migraine 11.3%, and of TTH 21.2%. The 1-year age- and sex-adjusted prevalence of migraine was 6.2%, of probable migraine 8.8%, and of TTH 20.7%; the prevalence of migraine combined with probable migraine was 15.0%. Total crude prevalence of headache (combination of migraine, probable migraine and TTH) was 39.9%. Prevalence of migraine was higher in continental than in Mediterranean areas of Croatia. Multivariate regression analysis showed that the highest risk of suffering from any kind of headache is observed for the following people: living in Dubrovnik, being female, having elementary or high school education, being married, employed and living in an urban or suburban area. CONCLUSION: The prevalence of migraine and probable migraine is similar as in other Western countries. Certain demographic characteristics differ among patients with and without headache.

Thrombosis of sinus sagitalis during puerperium caused by thrombophilic gene mutation.

Cerebral veno-sinus thrombosis (CVT) during puerperium may have fatal consequences. A nonspecific clinical picture must be complete with computed tomography of the brain and digital substract angiography of the brain blood vessels, and, once the clinical diagnosis is confirmed, coagulation tests and genetic analysis of the coagulation factor are to be made as well. Genetic polymorphisms associated with thrombophilia such as factor V Leiden, prothrombin G20210A, MTHFR C677T, ACE and PIA1/A2 may be the cause of the hypercoagulability that results in CVT.