MxA mRNA decrease preceding NAb detection in IFNß-treated MS patients.

BACKGROUND: Multiple sclerosis (MS) patients treated with interferon beta (IFNß) are at risk of a declining response to treatment because of the production of IFNß-neutralizing antibodies (NAbs). The expression of Myxovirus resistance protein A (MxA) mRNA is regarded as a marker of IFNß bioactivity. AIMS: The aim of this study was to analyze the kinetics of MxA mRNA expression during long-term IFNß treatment and assess its relationship to NAb production. METHODS: A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFNß treatment. NAbs and MxA mRNA were monitored every six months. RESULTS: 119 patients were consecutively enrolled and 107 were included in the final analysis. Both the presence of NAbs and a decrease in MxA mRNA below the cut off were revealed in 15 patients, however, in six patients (40%) positivity for NAbs was preceded by the decrease in MxA mRNA. In addition, a further six patients showing a decline in MxA mRNA did not have detectable NAbs. CONCLUSION: Our data indicate that quantification of MxA mRNA is a more sensitive identifier of loss of IFNß efficacy than the NAb positivity.

Myxovirus Resistance Protein A mRNA Expression Kinetics in Multiple Sclerosis Patients Treated with IFNß.

INTRODUCTION: Interferon-ß (IFNß) is the first-line treatment for relapsing-remitting multiple sclerosis. Myxovirus resistance protein A (MxA) is a marker of IFNß bioactivity, which may be reduced by neutralizing antibodies (NAbs) against IFNß. The aim of the study was to analyze the kinetics of MxA mRNA expression during long-term IFNß treatment and assess its predictive value. METHODS: A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFNß treatment. MxA mRNA was assessed prior to initiation of IFNß therapy and every three months subsequently. NAbs were assessed every six months. Assessment of relapses was scheduled every three months during 24 months of follow up. The disease activity was correlated to the pretreatment baseline MxA mRNA value. In NAb negative patients, clinical status was correlated to MxA mRNA values. RESULTS: 119 patients were consecutively enrolled and 107 were included in the final analysis. There was no correlation of MxA mRNA expression levels between baseline and month three. Using survival analysis, none of the selected baseline MxA mRNA cut off points allowed prediction of time to first relapse on the treatment. In NAb negative patients, mean MxA mRNA levels did not significantly differ in patients irrespective of relapse status. CONCLUSION: Baseline MxA mRNA does not predict the response to IFNß treatment or the clinical status of the disease and the level of MxA mRNA does not correlate with disease activity in NAb negative patients.

Transplantation of Mesenchymal Stromal Cells in Patients With Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial.

Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 ± 4.5 × 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application (p < 0.02) that, in some cases, persisted for 6 months ( p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease.

Odor identification in frontotemporal lobar degeneration subtypes.

Odor identification impairment is a feature of several neurodegenerative disorders. Although neurodegenerative changes in the frontotemporal lobar degeneration (FTLD) subtypes involve areas important for olfactory processing, data on olfactory function in these patients are limited. An 18-item, multiple-choice odor identification test developed at our memory clinic, the Motol Hospital smell test, was administered to 9 patients with behavioral variant frontotemporal dementia, 13 patients with the language variants, primary nonfluent aphasia (n = 7) and semantic dementia (n = 6), and 8 patients with progressive supranuclear palsy. Compared to the control group (n = 15), all FTLD subgroups showed significant impairment of odor identification (P < .05). The differences between the FTLD subgroups were not significant. No correlation between odor identification and neuropsychological tests results was found. Our data suggest that odor identification impairment is a symptom common to FTLD syndromes, and it seems to be based on olfactory structure damage rather than cognitive decline.

The bleeding risk during warfarin therapy is associated with the number of variant alleles of CYP2C9 and VKORC1 genes.

BACKGROUND: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. AIM: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. METHODS: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. RESULTS: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B. CONCLUSION: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.

Disturbance of real space navigation in moderately advanced but not in early Huntington's disease.

BACKGROUND: Visuospatial skills including spatial navigation are known to be impaired in Huntington's disease. Spatial navigation comprises two navigational frameworks, allocentric and egocentric. Several studies have associated the allocentric navigation with the hippocampus and the egocentric navigation with the striatum. The striatum is predominantly impaired from the early stages of Huntington's disease. OBJECTIVE: To find whether spatial navigation impairment is present in the early stages of Huntington's disease and to test the hypothesis that the egocentric navigation is predominantly affected compared to the allocentric navigation. METHODS: In nineteen patients with Huntington's disease the egocentric and the allocentric navigation skills were tested using the Blue Velvet Arena, a human analog of Morris Water Maze, and compared to nineteen age and gender-matched healthy controls. Cognitive functions, with emphasis on the executive functions, were also assessed. RESULTS: The spatial navigation skills deteriorated with the increasing motor impairment in Huntington's disease. These changes only became apparent in patients with moderate functional impairment. No difference between the egocentric and the allocentric skills was seen. DISCUSSION: Spatial navigation deficit is not an early marker of the cognitive dysfunction in Huntington's disease. We speculate that the striatal circuitry that is known to degenerate early in the course of Huntington's disease is not directly associated with the spatial navigation.

Spatial navigation and APOE in amnestic mild cognitive impairment.

BACKGROUND: The effect of APOE ε4 allele (ε4) on spatial navigation in amnestic mild cognitive impairment (aMCI) is unknown. OBJECTIVE: Our purpose was to examine the characteristics of spatial navigation impairment in ε4-positive (ε4+) and ε4-negative (ε4-) aMCI subgroups. METHODS: Blood samples were collected to determine the APOE genotype. A total of 34 aMCI patients were stratified into aMCI-ε4- (n = 23) and aMCI-ε4+ (n = 11) groups. Control (n = 28) and mild Alzheimer's disease (AD; n = 16) groups were also used. We used a human analogue of the Morris water maze (enclosed arena 2.9 m in diameter) to examine body-centered (egocentric) and world-centered (allocentric) spatial navigation. RESULTS: The aMCI-ε4+ group performed poorer on spatial navigation than the aMCI-ε4- group in both egocentric and allocentric tasks even though these 2 groups did not differ in global cognitive functioning or neuropsychological tests. The aMCI-ε4+ and mild AD groups performed similarly on all Morris Water Maze tasks and were outperformed by the aMCI-ε4- group, which also resembled the control group in performance on the egocentric tasks. The aMCI groups showed poor spatial navigation learning regardless of their ε4 positivity. CONCLUSION: We found more profound deficits in spatial navigation in aMCI-ε4+ relative to aMCI-ε4- patients. The aMCI-ε4+ group resembled the mild AD group in spatial navigation performance. Although the ε4 genotype was indicative of spatial navigation performance, it was not indicative of the aMCI patients' ability to learn the tasks. Spatial navigation testing represents a promising area with respect to identifying individuals at higher risk for AD among the heterogeneous MCI population.

Spatial navigation testing discriminates two types of amnestic mild cognitive impairment.

The hippocampus is essential for consolidation of declarative information and spatial navigation. Alzheimer's disease (AD) diagnosis tends to be preceded by a long prodromal period and mild cognitive impairment (MCI). Our goal was to test whether amnestic MCI comprises two different subgroups, with hippocampal and non-hippocampal memory impairment, that vary with respect to spatial navigation ability. A total of 52 patients were classified into two subgroups: non-amnestic MCI (naMCI) (n=10) and amnestic MCI (aMCI) (n=42). The aMCI subgroup was further stratified into memory impairment of hippocampal type-hippocampal aMCI (HaMCI) (n=10) (potential preclinical AD) and isolated retrieval impairment-non-hippocampal (NHaMCI) (n=32). Results were compared to control (n=28) and AD (n=21) groups. We used the Hidden Goal Task, a human analogue of the Morris Water Maze, to examine spatial navigation either dependent (egocentric) or independent of individual's position (allocentric). Overall, the HaMCI group performed poorer on spatial navigation than the NHaMCI group, especially in the latter trials when the HaMCI group exhibited limited capacity to learn and the NHaMCI group exhibited a learning effect. Finally, the HaMCI group performed almost identically as the AD group. Spatial navigation deficit is particularly pronounced in individuals with hippocampus-related memory impairment and may signal preclinical AD.

The epidural steroids in the prevention of epidural fibrosis: MRI and clinical findings.

BACKGROUND: Epidural fibrosis (EF) represents a frequent and poorly manageable complication of lumbar disk surgery. OBJECTIVES: To investigate the influence of perioperative Epidural Steroid (ES) application on the development of EF. METHODS: One hundred and seventy eight patients underwent L4/5 or L5/S1 discectomy. The study group receiving ES comprised of eighty five patients, and a further control group comprising eighty two patients received a placebo. At a 12 month follow-up, all subjects underwent contrast magnet resonance imaging of the lumbosacral spine. One hundred and sixty seven patients filled in a predetermined questionnaire containing the Visual Analogue Scale (VAS; pain scale) during the first postoperative days and 12 months after. Intergroup differences were analysed and a correlation between the extent of EF and VAS was examined. RESULTS: The groups did not differ regarding the extent of EF. There was a statistically significant correlation between the degree of fibrosis and VAS (P<0.05). However, there was no significant difference in subjective pain assessment between both groups 12 months postoperatively. The application of ES did not influence their return to work. Patients receiving ES experienced less pain on the first and third days after surgery. The average hospital stay after surgery was shorter in the steroid treated group (4.5 days) compared to 5.2 days in the control group (p<0.05). CONCLUSIONS: The application of ES did not prove to be useful in the prevention of Failed Back Surgery Syndrome and epidural scar formation. Postoperative pain was decreased in the steroid treated group during the first postoperative week, but not 12 months postoperatively.

Long lasting recurrent familiar transient global amnesia after betablocker treatment withdrawal: case report.

The etiology of Transient Global Amnesia (TGA) is not yet clear. A small part of TGA has a familiar occurrence. We report a case of recurrent, long-lasting familiar amnesia occurring after betablocker treatment withdrawal in a migrainous patient. We suggest that familiar TGA could be caused by the mechanism of vasospasm rather than venous congestion and that the abnormal cerebral vasomotor control could be the hereditary substrate in this condition.

[Detection of active varicella-zoster virus (VZV) infection in patients with neurological complications]. / Prukaz aktivní infekce virem varicella zoster (VZV) u pacientu s neurologickými komplikacemi.

OBJECTIVES: When introduced into routine virological diagnosis of nervous system infections, PCR detection of viral DNA revealed the varicella-zoster virus (VZV) in cerebrospinal fluid (CSF) at much higher rates than expected. The aim of the study was to evaluate the frequency of VZV DNA detection in CSF of patients with neurological symptoms in correlation with their VZV-specific serological findings and clinical symptoms. MATERIAL AND METHODS: A total of 438 patients followed up in the neurology departments of the Motol and Královské Vinohrady University Hospitals and the Department of Infectious Diseases of the Bulovka University Hospital were screened for the presence of VZV-specific antibodies in serum and intrathecal antibodies in CSF. A home-brew nested PCR assay was used for detection of VZV DNA in CSF. Positive results were correlated with clinical findings. RESULTS: Intrathecal antibodies against VZV were detected in 19.6 % of the studied patients, VZV-specific IgM antibodies were present in serum of 17.3 % of the patients and VZV DNA was recorded in CSF of 9.4 % of the patients. The clinical diagnosis was confirmed in 16 patients positive for VZV DNA in CSF: encephalitis as a complication of neonatal varicella in a 2-week child; encephalitis or meningoencephalitis in 5 adult patients of whom three had a history of herpes zoster, one suffered from severe haemorrhagic focal encephalitis with fatal complications and one had encephalitis and myelitis; neuropathies in 4 patients, two with inflammatory polyneuropathy of unknown origin and two with brachial plexopathy, in one case preceded by herpes zoster; epileptic symptoms in 2 patients; multiple sclerosis in 3 patients and nonspecific symptoms of chronic fatigue in one patient. CONCLUSIONS: 1) PCR proved to be a suitable method for diagnosing VZV-mediated nervous system infections. 2) VZV DNA can be present in CSF of patients with a wide range of neurological symptoms, even with no history of either herpes zoster or varicella. 3) VZV DNA detection in CSF needs to be interpreted with caution and in correlation with case histories, clinical findings and electrophysiological and imaging data, especially in patients with chronic inflammatory disease receiving immunosuppressive therapy.

Spatial navigation deficit in amnestic mild cognitive impairment.

Patients with Alzheimer's disease (AD) frequently have difficulties with spatial orientation in their day-to-day life. Although AD is typically preceded by amnestic mild cognitive impairment (MCI), spatial navigation has not yet been studied in MCI. Sixty-five patients were divided into five groups: probable AD (n = 21); MCI, further classified as amnestic MCI single domain (n = 11); amnestic MCI multiple domain (n = 18), or nonamnestic MCI (n = 7), and subjective memory complaints (n = 8). These patients, together with a group of healthy control subjects (n = 26), were tested by using a four-subtests task that required them to locate an invisible goal inside a circular arena. Each subtest began with an overhead view of the arena showed on a computer monitor. This was followed by a real navigation inside of the actual space, an enclosed arena 2.9 m in diameter. Depending on the subtest, the subjects could use the starting position and/or cues on the wall for navigation. The subtests thus were focused on allocentric and egocentric navigation. The AD group and amnestic MCI multiple-domain group were impaired in all subtests. The amnestic MCI single-domain group was impaired significantly in subtests focused on allocentric orientation and at the beginning of the real space egocentric subtest, suggesting impaired memory for allocentric and real space configurations. Our results suggest that spatial navigation impairment occurs early in the development of AD and can be used for monitoring of the disease progression or for evaluation of presymptomiatic AD.

Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury.

Stem cell transplants into spinal cord lesions may help to improve regeneration and spinal cord function. Clinical studies are necessary for transferring preclinical findings from animal experiments to humans. We investigated the transplantation of unmanipulated autologous bone marrow in patients with transversal spinal cord injury (SCI) with respect to safety, therapeutic time window, implantation strategy, method of administration, and functional improvement. We report data from 20 patients with complete SCI who received transplants 10 to 467 days postinjury. The follow-up examinations were done at 3, 6, and 12 months after implantation by two independent neurologists using standard neurological classification of SCI, including the ASIA protocol, the Frankel score, the recording of motor and somatosensory evoked potentials, and MRI evaluation of lesion size. We compared intra-arterial (via catheterization of a. vertebralis) versus intravenous administration of all mononuclear cells in groups of acute (10-30 days post-SCI, n=7) and chronic patients (2-17 months postinjury, n=13). Improvement in motor and/or sensory functions was observed within 3 months in 5 of 6 patients with intra-arterial application, in 5 of 7 acute, and in 1 of 13 chronic patients. Our case study shows that the implantation of autologous bone marrow cells appears to be safe, as there have been no complications following implantation to date (11 patients followed up for more than 2 years), but longer follow-ups are required to determine that implantation is definitively safe. Also, we cannot yet confirm that the observed beneficial effects were due to the cell therapy. However, the outcomes following transplantation in acute patients, and in one chronic patient who was in stable condition for several months prior to cell implantation, are promising. It is evident that transplantation within a therapeutic window of 3-4 weeks following injury will play an important role in any type of stem cell SCI treatment. Trials involving a larger population of patients and different cell types are needed before further conclusions can be drawn.

A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy.

This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg) 2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming previous observation.