The modified DYMUS questionnaire is a reliable, valid and easy-to-use tool in the assessment of dysphagia in multiple sclerosis.

BACKGROUND AND PURPOSE: Many patients with multiple sclerosis (MS) present swallowing difficulties. Dysphagia is associated with significant morbidity and mortality, has a profound impact on the quality of life but is under-reported by patients. The objective was to investigate the psychometric properties of the Dysphagia in Multiple Sclerosis (DYMUS) questionnaire and examine whether item reduction improves them. METHODS: The participants, 153 patients with MS and 104 healthy controls, completed the DYMUS and the Eating Assessment Tool 10 (EAT-10). The study consisted of factor, reliability and validity analysis of DYMUS, and item reduction, reliability, validity analysis and normative data generation for the modified DYMUS (mod-DYMUS). RESULTS: The internal consistency of DYMUS was excellent (Cronbach's alpha 0.886). Test-retest reliability was good for all the items. Factor and reliability analysis, along with other psychometric features, supported item reduction. The mod-DYMUS (consisting of items 1 and 3-7) showed improved internal consistency (Cronbach's alpha 0.903) and inter-item correlation coefficients (0.558-0.657), good test-retest reliability, excellent criterion validity and improved convergent validity. Patients had significantly higher mean mod-DYMUS score than controls (P < 0.001), and dysphagic patients (EAT-10 ≥ 3) had significantly higher mod-DYMUS than non-dysphagic patients (P < 0.001). A strong positive and significant correlation was noted between the mod-DYMUS and the EAT-10 (P < 0.001). A mod-DYMUS score of 1 or higher indicates dysphagia. CONCLUSIONS: Item reduction improves the psychometric properties of DYMUS. The mod-DYMUS is a valid, reliable, low-burden, screening tool for the detection of dysphagia in MS, which can enhance personalized assessment and guide management decisions that better respond to individual patients' needs.

Long-term effects of prolonged-release fampridine in cognitive function, fatigue, mood and quality of life of MS patients: The IGNITE study.

BACKGROUND: Studies have reported conflicting results regarding the potential benefit of prolonged release (PR) fampridine in other domains besides walking. Moreover, only a small number of studies have explored long- term effects of PR fampridine. The aim of this study was to assess cognitive function, quality of life, mood and fatigue in MS patients treated with fampridine after 6 and 12 months of treatment. METHODS: IGNITE was an observational, open label study. Subjects were examined with the timed 25-ft walk (T25FW) and the BICAMS battery and were asked to complete the Multiple Sclerosis Impact Scale (MSIS-29), Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory-II (BDI-II) and MS International Quality-of-Life questionnaire (MUSIQOL) at baseline and at weeks 24 and 48. Patients were sub-grouped into responders (n:40) and non-responders (n:20) according to T25FW performance after 2 weeks on treatment. RESULTS: After 6 months, statistically significant improvement was observed on T25FW (p < .001), SDMT (p < .001) and MSIS29 (p < .001), for responders. After 1 year on treatment, statistically significant improvement was observed in T25FW (p < .001), MSIS29 (p = .004), SDMT (p < .001) and MUSIQOL (p = .03) for responders. There were no statistically significant improvements for the non-responders. CONCLUSIONS: PR Fampridine may have a beneficial effect on information processing speed though not on memory. Study data provide some evidence that fampridine treatment may reduce the impact of MS on daily activities and improve quality of life but has no effect on subjective fatigue and mood.

White matter hyperintensities in myotonic dystrophy type 2: Not always another expression of the disease.

Myotonic dystrophy type 2(DM2), inherited in an autosomal, dominant manner, is clinically characterized by muscle weakness, variable myotonia, cataract and multiorgan involvement, including the Central Nervous System. Recent data from literature indicate a possible autoimmune susceptibility of patients with DM2, while white matter abnormalities are a common feature of the disease. We report herein the case of a 38-year old woman, with the rare co-existence of DM2 and MS and argue about the challenging differential diagnosis if CNS involvement is present in DM2 patients. Thus, is it another expression of a multisystem disorder or an unfortunate pure coincidence?

Viruses and endogenous retroviruses in multiple sclerosis: From correlation to causation.

Multiple sclerosis is an immune-mediated disease with an environmental component. According to a long-standing but unproven hypothesis dating to initial descriptions of multiple sclerosis (MS) at the end of the 19th century, viruses are either directly or indirectly implicated in MS pathogenesis. Whether viruses in MS are principally causal or simply contributory remains to be proven, but many viruses or viral elements-predominantly Epstein-Barr virus, human endogenous retroviruses (HERVs) and human herpesvirus 6 (HHV-6) but also less common viruses such as Saffold and measles viruses-are associated with MS. Here, we present an up-to-date and comprehensive review of the main candidate viruses implicated in MS pathogenesis and summarize how these viruses might cause or lead to the hallmark demyelinating and inflammatory lesions of MS. We review data from epidemiological, animal and in vitro studies and in doing so offer a transdisciplinary approach to the topic. We argue that it is crucially important not to interpret "absence of evidence" as "evidence of absence" and that future studies need to focus on distinguishing correlative from causative associations. Progress in the MS-virus field is expected to arise from an increasing body of knowledge on the interplay between viruses and HERVs in MS. Such interactions suggest common HERV-mediated pathways downstream of viral infection that cause both neuroinflammation and neurodegeneration. We also comment on the limitations of existing studies and provide future research directions for the field.

A case of CD30+ ALK1- anaplastic large cell lymphoma resembling acute disseminated encephalomyelitis.

Central nervous system involvement is an uncommon complication of systemic non-Hodgkin lymphomas. The majority of these cases concern B-cell lymphomas. We report a case of systemic T-cell anaplastic large cell lymphoma CD30+ ALK- with CNS involvement at the time of diagnosis and unusual MRI characteristics resembling acute disseminated encephalomyelitis.

Platelet-rich plasma in otolaryngology.

BACKGROUND: Platelet-rich plasma is a novel material that is being used more frequently in many surgical specialties. METHODS: A literature review on the current and potential uses of platelet-rich plasma in otolaryngology was performed. RESULTS: There is limited evidence on the use of platelet-rich plasma in otolaryngology compared with other specialties: only 11 studies on various subspecialties (otology, rhinology and laryngology) were included in the final review. CONCLUSION: Based on the limited number of studies, we cannot draw safe conclusions about the value of platelet-rich plasma in otolaryngology. Nevertheless, the available literature suggests that platelet-rich plasma holds promise for future research and may have a number of clinical applications.

CADASIL presenting with spontaneous intracerebral hemorrhage: report of a case and description of the first family in Northern Greece.

INTRODUCTION: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), the most common inherited cause of stroke and dementia in adults, has been described in six Greek families. Common presenting manifestations include migraine with aura, brain ischemia, mood disorders and cognitive decline. Spontaneous intracerebral hemorrhage (SICH) rarely occurs in CADASIL and only exceptionally as the first clinical manifestation. CASE DESCRIPTION: We have previously reported the sixth Greek family with CADASIL and in particular, two brothers in whom the genetic testing documented a classic mutation of the NOTCH3 gene (Arg169Cys). In this report, we describe the 30-year-old son of the second brother, who suffered a thalamic SICH as the presenting manifestation of CADASIL, in the absence of arterial hypertension or antiplatelet drug use. CONCLUSION: Patients with acute subcortical infarcts, leukoencephalopathy, a history of migraine, mood disorders, and dementia, should always raise the suspicion of CADASIL. However, a SICH, even in the absence of classical risk factors for hemorrhage, is possible and should not exclude the diagnosis of CADACIL. Hippokratia 2016, 20(1): 76-79.

Validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in Greek population with multiple sclerosis.

BACKGROUND: Cognitive impairment is experienced by about 50% of patients with Multiple Sclerosis (MS) worldwide and affects their employment, disease management and quality of life in general. The Brief International Cognitive assessment for MS (BICAMS) is a brief, practical and potentially universal battery for cognitive impairment in MS patients. It consists of three tests: the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT-2) and the Brief Visuospatial Memory Test-Revised (BVMT-R). OBJECTIVE: The objective of this study was to validate the BICAMS in Greek MS patients and controls. METHODS: Forty four MS patients and seventy nine healthy control (HC) participants were recruited and tested. They were group matched for age, education, gender and also premorbid cognitive reserve. All of them completed the three tests of the BICAMS battery. Instead of CVLT-2, the Greek validated form (Greek Verbal Learning Test, GVLT), was used. In addition, cognitive reserve was assessed using the Cognitive Reserve Index questionnaire (CRIq) standardized for the Greek population. RESULTS: Significant difference was found in the performance of the two groups in all tests (p<0.0001, p<0.02, p<0.009 for SDMT, GVLT and BVMT-R respectively). Test-retest reliability was good for all the tests. Based on the criterion of 1 or more tests below the 5th percentile of healthy controls performance, 47% of patients were found impaired. CONCLUSIONS: The study provides validation of BICAMS in Greek population and therefore facilitates the use of this battery in clinical practice and in future studies of MS patients in Greece.

Sexual divergence in microtubule function: the novel intranasal microtubule targeting SKIP normalizes axonal transport and enhances memory.

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, is a frequent autism spectrum disorder (ASD)-mutated gene. ADNP associates with microtubule end-binding proteins (EBs) through its SxIP motif, to regulate dendritic spine formation and brain plasticity. Here, we reveal SKIP, a novel four-amino-acid peptide representing an EB-binding site, as a replacement therapy in an outbred Adnp-deficient mouse model. We discovered, for the first time, axonal transport deficits in Adnp(+/-) mice (measured by manganese-enhanced magnetic resonance imaging), with significant male-female differences. RNA sequencing evaluations showed major age, sex and genotype differences. Function enrichment and focus on major gene expression changes further implicated channel/transporter function and the cytoskeleton. In particular, a significant maturation change (1 month-five months) was observed in beta1 tubulin (Tubb1) mRNA, only in Adnp(+/+) males, and sex-dependent increase in calcium channel mRNA (Cacna1e) in Adnp(+/+) males compared with females. At the protein level, the Adnp(+/-) mice exhibited impaired hippocampal expression of the calcium channel (voltage-dependent calcium channel, Cacnb1) as well as other key ASD-linked genes including the serotonin transporter (Slc6a4), and the autophagy regulator, BECN1 (Beclin1), in a sex-dependent manner. Intranasal SKIP treatment normalized social memory in 8- to 9-month-old Adnp(+/-)-treated mice to placebo-control levels, while protecting axonal transport and ameliorating changes in ASD-like gene expression. The control, all d-amino analog D-SKIP, did not mimic SKIP activity. SKIP presents a novel prototype for potential ASD drug development, a prevalent unmet medical need.

A basic overview of multiple sclerosis immunopathology.

Multiple sclerosis (MS) is a multi-component disease characterized by inflammation, neurodegeneration and failure of central nervous system (CNS) repair mechanisms. Immune dysregulation appears to originate with dendritic cells (antigen-presenting cells) which have an activated phenotype in individuals with MS. Dendritic cells migrate across the blood-brain barrier and induce differentiation of memory T cells into pro-inflammatory T helper 1 (Th1) and Th17 lymphocytes. In turn, induction of macrophage and microglial activation produces other pro-inflammatory cytokines and oxygen and nitric oxide radicals responsible for the demyelination and axonal loss. Other known mediators of MS pathology include CD8+ T cells and memory B cells within the CNS. Some pathological hallmarks of MS are early axonal degeneration and progressive decline of brain volume in patients with clinically isolated syndromes who progress to clinically definite MS. Many new options to interfere with the course of MS have become available in recent years. To limit inflammatory demyelinating processes and delay disease progression, intervention to control inflammation must begin as early as possible. Each distinct type of immunotherapy (immunomodulation, immunosuppression and immune-selective intervention - blockade type, sequestering type or depleting type) corresponds to a specific underlying immunopathology of MS.

Neuroprotective and anti-inflammatory mechanisms are activated early in optic neuritis.

OBJECTIVE: The aim of the study was to investigate the expression of different immunological mediators in blood and CSF in patients with acute ON and to estimate whether they were implicated in pro- or anti-inflammatory or even regulatory reactions in comparison with a healthy control group (HC). METHODS: Sixty-four patients between 18 and 59 years of age suffering by acute ON, onset of <4 weeks, were included in the study. Visual tests and brain magnetic resonance imaging (MRI) were performed in ON. Blood and CSF samples were collected from untreated patients and from a gender- and age-matched voluntary HC (n = 32). The mRNA expression of distinct cytokines and neurotrophic factors was assessed by semi/quantitative real-time PCR (RT-PCR). RESULTS: Brain- and glial cell-derived neurotrophic factor (BDNF and GDNF) and interleukin 10 (IL-10) expression was significantly increased in the CSF compared to the blood in both ON and HC (P < 0.001). In the CSF increased levels of BDNF and GDNF of the ON group were positively correlated with the presence of oligoclonal bands (OB). Additionally, patients with gadolinium (gd+) lesions on brain MRI showed increased levels of IL-5 in blood (P = 0.03). CONCLUSION: Our data indicate that both immuno-regulatory and neuroprotective mechanisms may potentially take place relatively early in the course of the ON. The presence of neurotrophic factors in healthy CSF and their overexpression already during the acute phase of ON supports the alertness of CNS defence mechanisms ready to be activated during degenerative events, such as destruction of the myelin.

Coexistence of multiple sclerosis and ankylosing spondylitis: report of two cases.

BACKGROUND: Multiple sclerosis (MS) only rarely coexists with ankylosing spondylitis (AS). The optimal management of these patients represents a major challenge. METHODS: In the present study, we report 2 cases of AS with definite MS comorbidity. One of the AS-MS cases had received anti-TNFα treatment, which was discontinued due to exacerbation of the MS. In addition, we discuss 3 more AS cases with neurological symptoms and atypical white matter demyelinating MRI lesions after anti-TNFα treatment. DISCUSSION: Given the fact that anti-TNFα drugs can potentially exacerbate a latent MS or induce atypical demyelination in the central nervous system, they should be discouraged or discontinued in relevant cases. The remaining effective therapeutic options for MS are either contradictory for AS (interferon-ß), have no definite data regarding their safety/efficacy in AS (glatiramer acetate, azathioprine, natalizumab, fingolimod), or their efficacy in MS-AS is associated with increased treatment risks (rituximab). Any of these proposed treatments may require active patient's informed consent.

A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis.

WHAT IS KNOWN AND OBJECTIVE: The relative effectiveness and safety profile of the treatments with marketing authorization for relapsing multiple sclerosis (MS) are not well known because randomized controlled trials with head-to-head comparisons between these treatments do not exist. Thus, a network of multiple-treatments meta-analysis was performed using four clinical outcomes: 'patients free of relapse', 'patients without disease progression', 'patients without MRI progression' and 'patients with adverse events'. METHODS: Randomized controlled trials (RCTs) on MS were systematically searched in PubMed and Cochrane Central Register of Controlled Trial. The network analysis performed pairwise comparisons between the marketed treatments (Betaferon 250mcg, Avonex 30mcg, Rebif 44mcg, Rebif 22mcg, Aubagio 7 mg, Aubagio 14 mg, Copaxone 20 mg, Tysabri 300 mg, Gilenya 0·5 mg and Novantrone 12 mg/m(2)) using direct and indirect analyses. RESULTS AND DISCUSSION: The analysis included 48 articles, involving 20 455 patients with MS. The direct analysis showed better response for more than one outcome for Gilenya compared with Avonex ('patients free of relapse' and 'patients without MRI progression') and for Betaferon compared with Avonex ('patients without disease progression' and 'patients without MRI progression'). The indirect analysis indicated that Tysabri may have better relative effectiveness compared with the other treatments for two outcomes: 'patients free of relapse' and 'patients without MRI progression'. Regarding 'patients with adverse events', no data were available for all comparisons to make fair inferences. WHAT IS NEW AND CONCLUSION: This was an attempt, for the first time, to compare the efficacy and safety profile of existing approved treatments for relapsing MS. Although some treatments have shown better response, the results of the network analysis should be interpreted with caution because of the lack of RCTs with head-to-head comparisons between treatments.

Acute inflammation alters adult hippocampal neurogenesis in a multiple sclerosis mouse model.

Neural precursor cells (NPCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) give rise to thousands of new cells every day, mainly hippocampal neurons, which are integrated into existing neuronal circuits. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of inflammation is somewhat controversial. The present study demonstrates that the inflammatory environment prevailing in the brain of experimental autoimmune encephalomyelitis (EAE) mice enhances the proliferation of NPCs in SGZ of the dorsal DG and alters the proportion between radial glial cells and newborn neuroblasts. The injection protocol of the cell cycle marker bromodeoxyuridine and the immunohistochemical techniques that were employed revealed that the proliferation of NPCs is increased approximately twofold in the SGZ of the dorsal DG of EAE mice, at the acute phase of the disease. However, although EAE animals exhibited significant higher percentage of newborn radial-glia-like NPCs, the mean percentage of newborn neuroblasts rather was decreased, indicating that the robust NPCs proliferation is not followed by a proportional production of newborn neurons. Significant positive correlations were detected between the number of proliferating cells in the SGZ and the clinical score or degree of brain inflammation of diseased animals. Finally, enhanced neuroproliferation in the acute phase of EAE was not found to trigger compensatory apoptotic mechanisms. The possible causes of altered neurogenesis observed in this study emphasize the need to understand more precisely the mechanisms regulating adult neurogenesis under both normal and pathological conditions.

Pseudo-quadriceps sparing in multiple sclerosis.

BACKGROUND: Sparing of the quadriceps muscle has been reported in various myopathies. In multiple sclerosis (MS) and pyramidal syndromes, in general, such a differential involvement of distinct muscle groups has not been described. METHODS: Muscle power was evaluated in 127 patients with chronic pyramidal syndrome caused by MS and 37 patients with acute or chronic paraparesis from other etiologies (mainly cerebro-vascular events). RESULTS: A striking difference in muscle power of the quadriceps (spared) and the iliopsoas (significantly weakened) was found in the patients suffering from chronic pyramidal syndrome caused by MS. The mean muscle power of the iliopsoas was 1.68±1.1 and that of the quadriceps 4.06±1.4 (P<0.00005). In the control group, the mean muscle power was 2±1.2 and 2.4±1.4 (difference not significant), for the iliopsoas and the quadriceps, respectively. CONCLUSIONS: Quadriceps muscle remains relatively spared in patients with MS, even with severe and long-standing paraparesis. Various neuroanatomical, neurophysiological, and rehabilitational mechanisms may be involved and explain this phenomenon. This observation may contribute to the building of more reliable and linear scales for the assessment of motor disability and disease progression in MS.

Predictable ventricular shift after focal cerebral ischaemia in rats: practical considerations for intraventricular therapeutic interventions.

Intracerebroventricular (ICV) route of administration is a useful experimental method to study the effects of chemicals or cellular grafts in the ventricular compartment of the brain after focal ischaemia. However, the induced oedema may cause structural dislocating phenomena and render a stereotaxic ICV invasion difficult and practically unavailable especially during the acute post-ischaemia phase. The aim of this study was to measure these structural ventricular dislocations and set new stereotaxic coordinates for successful and cost-effective ICV invasion 6-18 h after focal cerebral ischaemia. Wistar rats were subjected to 2 h middle cerebral artery occlussion (t-MCAO), were neurologically evaluated (modified Neurological Stroke Scale [mNSS], modified Bederson's Scale [mBS] and grid-walking test [GWT]) and brain slides were studied at 6 and 18 h post-occlusion for infarction volume, hemispheric oedema, middle line dislocation and stereotaxia of the lateral ventricles. Our data indicated that stereotaxic coordinates of the lateral ventricles in the infarcted and contralateral hemispheres significantly (P < 0.05) changed at both time-points and were linearly correlated with the mNSS, mBS and some GWT scores (P < 0.001). This correlation allowed for the calculation of simple (linear) mathematical equations (stereotaxic coordinate = b0 + b1*mNSS, where 'b0' and 'b1' are fixed number and factor, respectively, calculated by regression analysis) that determined individually new coordinates for each animal. Verification experiments revealed that the new coordinates render ICV invasion feasible in up to 80% of infarcted rats (number needed to treat 1.65), compared with only 19.4% using the classical coordinates for normal rats. Therefore, we propose a new, time- and cost-effective methodology for practically feasible ICV invasion in rats 6-18 h after t-MCAO.