Prolonged-release fampridine in multiple sclerosis: clinical data and real-world experience – report of an expert meeting

Prolonged-release (PR) fampridine is the only approved medication to improve walking in multiple sclerosis (MS), having been shown to produce a clinically meaningful improvement in walking ability in the subset of MS patients with Expanded Disability Status Scale 4-7. Recent responder subgroup analyses in the phase III ENHANCE study show a large effect size in terms of an increase of 20.58 points on the patient-reported 12-item MS Walking Scale in the 43% of patients classified as responders to PR-fampridine, corresponding to a standardized response mean of 1.68. Use of PR-fampridine in clinical practice varies across Europe, depending partly on whether it is reimbursed. A group of European MS experts met in June 2017 to discuss their experience with using PR-fampridine, including their views on the patient population for treatment, assessment of treatment response, re-testing and re-treatment, and stopping criteria. This article summarizes the experts' opinions on how PR-fampridine can be used in real-world clinical practice to optimize the benefits to people with MS with impaired walking ability.info:eu-repo/semantics/publishedVersio

Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study

Background A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. Patients and methods From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Results Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. Conclusions In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment

The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes

The relationship between late normal tissue radiation injury phenotypes in 167 breast cancer patients treated with radiotherapy and: (i) radiotherapy dose (boost); (ii) an early acute radiation reaction and (iii) genetic background was examined. Patients were genotyped at single nucleotide polymorphisms (SNPs) in eight candidate genes. An early acute reaction to radiation and/or the inheritance of the transforming growth factor-β1 (TGFβ1 −509T) SNP contributed to the risk of fibrosis. In contrast, an additional 15 Gy electron boost and/or the inheritance of X-ray repair cross-complementing 1 (XRCC1) (R399Q) SNP contributed to the risk of telangiectasia. Although fibrosis, telangiectasia and atrophy, all contribute to late radiation injury, the data suggest that they have distinct underlying genetic and radiobiological causes. Fibrosis risk is associated with an inflammatory response (an acute reaction and/or TGFβ1), whereas telangiectasia is associated with vascular endothelial cell damage (boost and/or XRCC1). Atrophy is associated with an acute response, but the genetic predisposing factors that determine the risk of an acute response or atrophy have yet to be identified. A combined analysis of two UK breast cancer patient studies shows that 8% of patients are homozygous (TT) for the TGFβ1 (C-509T) variant allele and have a 15-fold increased risk of fibrosis following radiotherapy (95% confidence interval: 3.76–60.3; P=0.000003) compared with (CC) homozygotes

TC II deficiency: avoidance of false-negative molecular genetics by RNA-based investigations

Transcobalamin II (TC II) is a plasma transport protein for cobalamin. TC II deficiency can lead to infant megaloblastic anemia, failure to thrive and to neurological complications. This report describes the genetic work-up of three patients who presented in early infancy. Initially, genomic investigations did not reveal the definite genetic diagnosis in the two index patients. However, analysis of cDNA from skin fibroblasts revealed a homozygous deletion of exon 7 of the TC II gene caused by the mutation c.940+303_c.1106+746del2152insCTGG (r.941_1105del; p.fs326X) in one patient. The other patients were siblings and both affected by an insertion of 87 bp on the transcript which was caused by the homozygous mutation c.580+624A>T (r.580ins87; p.fs209X). Additional experiments showed that cDNA from lymphocytes could have been used also for the genetic work-up. This report shows that the use of cDNA from skin fibroblasts or peripheral lymphocytes facilitates genetic investigations of suspected TC II deficiency and helps to avoid false-negative DNA analysis

Cerebellum and source memory

We report the case of a 40-year-old right-handed German-speaking man who presented with ischemic stroke in the territories of the right superior cerebellar artery and posterior inferior cerebellar artery. The objective of the present study was to investigate the consequences of this cerebellar damage with regard to higher cognitive functions. On admission to the stroke unit, the patient presented with dysarthria, right-sided appendicular ataxia, gait ataxia, and right-sided horizontal nystagmus (National Institutes of Health Stroke Scale, NIHSS, score 4). When examined 10 days after his stroke using a set of neuropsychological tests, he showed a marked deficit in the ability to remember when and in which context he had previously encountered verbal material. This aspect of memory, so-called 'source memory', is known to be mediated mainly by frontal and medial temporal structures. The present case suggests the existence of a strong functional connectivity between cerebellum and cortical regions underlying specific memory processes

Antiepileptic drugs interact with folate and vitamin B12 serum levels

OBJECTIVE: Antiepileptic drugs (AEDs) are important for the treatment of epilepsy, psychiatric diseases, and pain syndromes. Small studies have suggested that AED treatment reduces serum levels of folate and vitamin B12. METHODS: This prospective monocenter study aimed at testing the hypothesis that AED treatment is associated with folate and vitamin B12 serum levels in a large population. A total of 2730 AED-treated and 170 untreated patients with epilepsy and 200 healthy individuals were enrolled. RESULTS: Treatment with carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate was associated with lower mean serum folate levels or with a higher frequency of folate levels below the reference range in comparison with the entire group of patients, untreated patients, or controls. Treatment with phenobarbital, pregabalin, primidone, or topiramate was associated with lower vitamin B12 levels compared with the entire group of patients. Vitamin B12 serum levels were higher in patients treated with valproate compared with the entire group of patients, untreated patients, and healthy controls. Folate or vitamin B12 levels below the reference range were associated with higher mean corpuscular volume (MCV) and higher homocysteine plasma levels. Vitamin substitution for 3 months in 141 patients with folate or vitamin B12 levels below the reference range yielded normal vitamin levels in 95% of the supplemented patients and reduced MCV and homocysteine plasma levels. INTERPRETATION: Treatment with most of the commonly used AEDs is associated with reduced folate or vitamin B12 serum levels and is a risk factor for hyperhomocysteinemia. Oral substitution is effective to restore vitamin, MCV, and homocysteine levels. Ann Neurol 2011

Common genetic coagulation variants are not associated with ischemic stroke in a casecontrol study

OBJECTIVE: Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke. METHODS: Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G-->A and factor XIII Val34Leu. RESULTS: The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G-->A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke