Kappa free light chains is a valid tool in the diagnostics of MS: A large multicenter study.

OBJECTIVE: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). METHODS: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. RESULTS: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2-138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5-22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85-0.90) was higher than OCB (0.82; 95%CI = 0.79-0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78-0.88) was lower (OCB = 0.92; 95% CI = 0.89-0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. CONCLUSION: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.

A population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary.

BACKGROUND AND PURPOSE: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria. METHODS: A retrospective population-based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re-evaluation from multiple sources. Crude and sex- and serostatus-specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person-years) from 2006 to 2015 were estimated and age-adjusted rates were determined. RESULTS: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52-2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person-years provided an incidence rate of 1.32 (95% CI 1.08-1.61) per 1 000 000 person-years. Age-adjusted prevalence was 1.87 (95% CI 1.56-2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98-1.46) per 1 000 000 person-years. CONCLUSIONS: In this first report of a large population-based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

The use of enhanced intrinsic feedback for motor learning in stroke survivors: Clinical trial protocol.

BACKGROUND: Stroke can lead to lasting sensorimotor deficits of the upper limb (UL) persisting into the chronic phase despite intensive rehabilitation. A major impairment of reaching after stroke is a decreased range of active elbow extension, which in turn leads to the use of compensatory movements. Retraining movement patterns relies on cognition and motor learning principles. Implicit learning may lead to better outcomes than explicit learning. Error augmentation (EA) is a feedback modality based on implicit learning resulting in improved precision and speed of UL reaching movements in people with stroke. However, accompanying changes in UL joint movement patterns have not been investigated. The objective of this study is to determine the capacity for implicit motor learning in people with chronic stroke and how this capacity is affected by post-stroke cognitive impairments. METHODS: Fifty-two subjects who have chronic stroke will practice reaching movements 3×/wk. for 9 wk. in a virtual reality environment. Participants will be randomly allocated to 1 of 2 groups to train with or without EA feedback. Outcome measures (pre-, post- and follow-up) will be: endpoint precision, speed, smoothness, and straightness and joint (UL and trunk) kinematics during a functional reaching task. The degree of cognitive impairment, lesion profile, and integrity of descending white matter tracts will be related to training outcomes. CONCLUSIONS: The results will inform us which patients can best benefit from training programs that rely on motor learning and utilize enhanced feedback. TRIAL STATUS: Ethical approval for this study was finalized in May 2022. Recruitment and data collection is actively in progress and is planned to finish in 2026. Data analysis and evaluation will occur subsequently, and the final results will be published.

Kynurenines, redox disturbances and neurodegeneration in multiple sclerosis.

Multiple sclerosis (MS) is a chronic, demyelinating disease of unknown origin. Sophisticated analytical methods have made it possible to measure small biologically active molecules at low endogenous levels, and understand their role in the network of other biologically active compounds actively involved in inflammatory and neurodegenerative processes. Evidence is accumulating as concerns the disturbances of the kynurenine pathway and redox changes in MS. A new promising metabolite of the kynurenine pathway seems to beneficially influence experimental allergic encephalomyelitis. More clinical evidence is needed to prove the role of kynurenic acid analogues and/or enzyme inhibitors as potential medications in MS in the future. Various compounds have been shown to be important in the pathophysiological processes of the disease and are targets for pharmaceutical intervention.

[Diagnostic studies of cerebrospinal fluid in patients with multiple sclerosis]. / Liquordiagnosztikai vizsgálatok sclerosis multiplexes betegekben.

The diagnostic criteria postulated by Poser necessitate clinical and laboratory CSF analysis for establishment of the diagnosis of definitive multiple sclerosis. The present paper reports methods for CSF examinations relating to multiple sclerosis with regard to the examinations suggested by the Charcot Foundation. In the course of CSF analysis, it is important to discriminate between the immunoglobulins present in normal amounts, those synthesized locally in pathological quantities and those penetrating across the damaged blood-CSF barrier. Normally, a parallel assay of CSF and serum specimens is carried out in the course of quantitative and qualitative protein analysis. In 37 patients with clinical multiple sclerosis, we determined the albumin and the immunoglobulin classes IgG, IgA and IgM, using laser nephelometry. An elevated IgG index was found in 76% of the cases, which points to local IgG snythesis and might be proof of the humoral immune response. The albumin quotient, which is suitable for examination of the integrity of the blood-CSF barrier, was within the reference range. Qualitative protein analysis was performed by means of electrophoresis on agarose-gel and isoelectric focusing. Agarose-gel electrophoresis revealed oligoclonal gammopathy in 68%, in contrast with the 91% demonstrated by isoelectric focusing. Comparison of the two kids of qualitative protein analyses indicated that isoelectric focusing was more sensitive for the detection of oligoclonal bands, in support of the literature finding.

[Treatment of relapsing-remitting multiple sclerosis with interferon beta type 1-b]. / A relapszus-remisszió kórformájú sclerosis multiplexes betegek kezelése interferon-béta-1b-vel.

Interferon-beta-1b was the first drug found to slow the progression of relapsing-remitting multiple sclerosis, with a reported decrease in the relapse rate of up to 34%. The present study involved 35 patients treated with interferon-beta-1b for one year. The aims of the study were: a) to compare the changes in the relapse rate and the number of days of hospitalization with other data, b) to compare the steroid needs required to treat relapses for one year before and in the year of interferon-beta-1b treatment. Our data indicated that the relapse rate may decrease as much as 77% following the introduction of interferon-beta-1b treatment. The adverse effects and the changes in the EDSS grades were similar to the published data. The duration of hospitalization decreased by 84% and the amount of methylprednisolone needed for remission by 78%. This data suggest that the impairment of the condition of the patients may be delayed considerably, while some of them can continue to work for a longer period, the standard of life of these patients therefore being more tolerable.

Factors influencing the health-related quality of life in Hungarian multiple sclerosis patients.

BACKGROUND: The 'Multiple Sclerosis Quality of Life Instrument' (MSQOL-54) was recently validated in Hungarian, on more than 400 multiple sclerosis (MS) patients. The aim of the present study was to examine the impact on their overall quality of life (QoL) of the demographic and clinical data on these patients, and their scores on different QoL scales. METHODS: The Hungarian version of MSQOL-54 was given to patients at the outpatient units at the Department of Neurology, University of Szeged, and two other Hungarian MS centres. Additional data, including the EDSS scores of the patients, and relevant clinical and demographic data, were also collected. RESULTS: The questionnaire scales relating to social function, general health, mental health and satisfaction with the sexual function mostly determined the overall QoL ratings. 62.1% of the patients indicated at least one comorbid condition. Depressed patients had a significantly worse quality of life (p<0.0001). CONCLUSIONS: MSQOL-54 is a useful tool for the recognition of possibly treatable factors influencing the QoL, but not assessed by the EDSS. Quality of life data have emerged on more than 400 patients, i.e. a considerable proportion of the Hungarian MS patient population.

A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking.

There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained in single-center studies. Therefore, collaboration between investigators is needed to establish large biobanks of well-defined samples. Standardized protocols for biobanking are a prerequisite to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by preanalytical factors. Here, a consensus report on recommendations for CSF collection and biobanking is presented, formed by the BioMS-eu network for CSF biomarker research in multiple sclerosis. We focus on CSF collection procedures, preanalytical factors, and high-quality clinical and paraclinical information. The biobanking protocols are applicable for CSF biobanks for research targeting any neurologic disease.

Cross-cultural adaptation and validation of the 'Multiple Sclerosis Quality of Life Instrument' in Hungarian.

Health-related quality of life measurements are gaining more importance in the study and clinical practice of multiple sclerosis. The aim of our study was the adaptation of the Multiple Sclerosis Quality of Life Instrument (MSQOL-54) in Hungarian. The study was carried out at the Department of Neurology, University of Szeged and two other multiple sclerosis centers. The Hungarian translation of the questionnaire was given to patients at the outpatient units of the neurology departments. The EDSS score of the patients were determined and data concerning the onset and the clinical form of the disease was collected. Altogether 438 patients filled out the questionnaire. We enrolled patients with all clinical forms of the disease. Cronbach's alpha coefficients were over 0.8 in case of all scales except ;Rolelimitations - emotional' (0.794), indicating a good internal consistency reliability for group comparisons. The instrument was able to distinguish between known clinical group differences. The Hungarian version of the MSQOL-54 instrument shows good psychometric properties similar to the original questionnaire.

Epidemiology of familial multiple sclerosis in Hungary.

The prevalence of familial aggregation of multiple sclerosis (MS) is estimated between 5 and 10%. Studies emphasize the effect of genetic factors over the environment of the patients in the development of the disease. We investigated familial accumulation of MS in the cases of 1500 patients in five Hungarian MS centers. According to our data, the risk of familial MS in Hungary is lower than in other countries for which literature data are accessible. The literature does not contain any data for the prevalence of familial MS in Hungary and middle-eastern Europe.

Familial effects on the clinical course of multiple sclerosis.

BACKGROUND: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. METHOD: We evaluated 1,083 families with > or =2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. RESULTS: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa -0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs and no evidence for anticipation or effects of genetic loading. CONCLUSION: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.

The norepinephrine level is decreased in the lymphocytes of long-term interferon-beta-treated multiple sclerosis patients.

The mutual involvement of dopamine and its metabolites in the nervous and immune systems has the potential to provide information on the interaction of these two systems. During a 24-hour period, we used capillary electrophoresis with electrochemical detection to repeatedly measure the intracellular catecholamine concentrations in the peripheral blood lymphocytes of relapsing-remitting multiple sclerosis (RRMS) patients receiving interferon (IFN)-beta-1b (n = 13), and those of IFN-naïve RRMS patients receiving their first IFN-beta-1a injection (n = 19) during this study, and compared them with the levels in healthy controls (n = 12). At baseline, the norepinephrine level was significantly decreased (P =0.003) in the long-term IFN MS patients compared with the controls. The Time x Group interactions for dopamine (P=0.5854) and norepinephrine (P=0.6192) were not significant. The group effects for the individual drugs were P=0.3529 and 0.1282, respectively. The lower norepinephrine level at baseline in the long-term IFN MS group suggests an immunologically stable phase, in line with our previous findings. This is the first report of the effects of IFN-beta administration on intracellular catecholamines in MS patients. Further studies are necessary to elucidate the immune reactions affected by the catecholamines in MS and to evaluate the roles of these potential immunotransmitters.

Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients.

Tryptophan and its metabolites are of great interest in understanding the pathogenesis of multiple sclerosis (MS). The total levels of tryptophan and its metabolites, kynurenine and kynurenic acid were determined in plasma by capillary liquid chromatography electrospray ionisation tandem mass spectrometry. This is the first report of the plasma levels of these analytes in healthy controls and relapsing-remitting MS patients receiving long-term and acute interferon-beta (IFN-beta) treatment. Twenty-four hours post-administration increased kynurenine levels (first IFN MS versus healthy, P = 0.042) and kynurenine/tryptophan ratio (K/T; first IFN MS versus healthy, P =0.027; first IFN MS versus long-term IFN MS, P = 0.036) were found. The long-term IFN MS group had higher K/T ratios at 4 and 12 h post-administration (P = 0.015 and 0.009, respectively). The increase of K/T ratio in the first IFN MS group indicate an induction of the enzyme indolamine-2,3-dioxygenase (IDO), as reported earlier in experimental allergic encephalomyelitis. As IDO is participating in both inflammatory and neurodegenerative processes, further knowledge of its involvement in the pathogenesis of MS is of great importance.

Amino acids in the saliva of patients with migraine.

There are a number of hypotheses concerning the pathogenesis of migraine, but they are frequently conflicting. In addition to the vascular hypothesis, clinical data are available that excitatory amino acids may play an important role in the development of the disease. In this study, free amino acid concentrations were measured by RP-HPLC in the saliva of 23 migraineurs without aura, 14 migraineurs with aura, and 20 healthy subjects. Significantly higher concentrations of glutamic acid, serine, glycine, arginine, and tyrosine were found in the saliva samples of both groups of migraineurs relative to the control group. It is suggested that amino acids causing hyperexcitability in the central nervous system may be linked to the pathogenesis of migraine.

The prevalence of multiple sclerosis in the Hungarian city of Szeged.

OBJECTIVES: The aim of this study was to determine the prevalence of multiple sclerosis in a population in South Hungary. METHODS: The diagnosis was established with the aid of the Poser diagnostic criteria and the degree of physical disability was determined on the Kurtzke expanded disability status scale (EDSS). The present medical state (EDSS score) was determined from outpatient clinical control tests. The prevalence, the average age at onset of the disease and the proportions of the various clinical forms were calculated, and the patients' disability status was estimated. RESULTS: In 1996, the prevalence was 65/100,000, and the incidence from January 1, 1995 through December 31, 1996 was 7/100,000/year. DISCUSSION: During a period of 2 years, the number of diagnosed patients has almost doubled. The disease can be recognized in an early stage with a minimal neurological deficit. The development of the diagnostics necessitates re-examinations with modern diagnostic procedures. During the last 3 years, the general practitioner system has been reorganized, and the working relationships between the clinic and family doctors have developed considerably. A comparison of the present findings with those in other countries with a similar climate revealed very similar prevalence data.

A pilot study on the antibodies to HHV-6 variants and HHV-7 in CSF of MS patients.

In the possible role for human herpesviruses (HHV) in the pathogenesis of multiple sclerosis (MS) neither clear distinction between the two variants of HHV-6, nor the involvement of HHV-7 have been described. Therefore, we quantitated HHV-6 variant specific and HHV-7 reacting antibodies in the CSF of 13 patients with MS or other neurological disorders by ELISA. Predominance in the positivity of IgG (67%) and IgM (44%) to HHV-6B over that of IgG (44%) with no detectable IgM to HHV-6A, and no antibodies to HHV-7 were found in the CSF of MS patients. None of these antibodies were found in the CSF of controls. This suggests that, intrathecal chronic active or primary HHV-6B infection might contribute to MS progression, while the local effects of HHV-6A and HHV-7 seem to be less important.

The prevalence of multiple sclerosis, distribution of clinical forms of the disease and functional status of patients in Csongrád County, Hungary.

OBJECTIVE: The aim of this study was to determine the prevalence of multiple sclerosis (MS) in the population of Csongrád County, Hungary (400,128 inhabitants) and to determine the functional status (based on the Expanded Disability Status Scale; EDSS) of the patients according to the clinical forms of the disease. METHODS: The diagnosis was established with the aid of the Poser diagnostic criteria, and the degree of physical disability was determined using the Kurtzke EDSS. RESULTS: In Csongrád County, the prevalence of MS is 62/100,000. The distribution of patients according to the clinical forms of MS was as follows: 15% had the benign form, 54% had relapsing-remitting MS, 20% had secondary chronic progressive MS and 11% had the primary chronic progressive form of MS. Sixty percent of relapsing-remitting MS patients had an EDSS score of 0-4 points and 33% had an EDSS score of 4.5-6.5 points. CONCLUSION: The distribution of patients according to the clinical forms of the disease in this representative population is comparable to results in other regions of the world.

Familial multiple sclerosis: case study of three affected siblings.

We report on three sisters with new-onset multiple sclerosis (MS). The symptoms of the eldest sister began in 1993 with lower-limb weakness and paraesthesia. In 1998, she had limb weakness, nystagmus and ataxia. Magnetic resonance imaging (MRI) of the brain, the cerebrospinal fluid (CSF) examinations, and evoked potentials verified MS. The middle sister exhibited left-side optic neuritis in 1998. All findings pointed to MS. The third sister had subjective complaints such as paraesthesias and vertigo. MRI and CSF results supported the diagnosis. Both parents and all four grandparents are without neurological signs; the brain MRI examinations on the parents were negative. The prevalence of familial MS in first-degree relatives is 5-10%, while that in twins is 20-30%. In this case, environmental factors seem to play the crucial role. Although the anamnesis as concerns MS proved negative in the other family members examined here, further genetic examination of the sisters is needed.