Switch to ocrelizumab in MS patients treated with natalizumab in extended interval dosing at high risk of PML: A 96-week follow-up pilot study.

We aimed to assess the long-term safety and effectiveness of ocrelizumab in a cohort of patients with multiple sclerosis (MS) at high risk of progressive multifocal leukoencephalopathy (PML), previously treated with natalizumab in extending interval dosing (EID), who switched to ocrelizumab and to compare them with patients who continued EID-natalizumab. Thirty MS patients previously treated with natalizumab in EID (every 8 weeks) were included in this observational retrospective cohort study. Among them, 17 patients were switched to ocrelizumab and 13 continued with EID-natalizumab. Except for the John Cunningham virus (JCV) index, no significant differences were detected between both groups. Main outcome measures included: annualized relapse rate (ARR), radiological activity, disability progression, and the NEDA-3 index. Patients were followed for 96 weeks. The median washout period in ocrelizumab-switchers was 6 weeks. Among them, AAR and radiological activity during follow-up were 0.03, without significant differences in comparison with the previous period on natalizumab-EID. The comparison between ocrelizumab-switchers and patients continuing on EID-natalizumab showed no significant differences in AAR, radiological activity, or disability progression. However, the proportion of patients maintaining a NEDA-3 status in week 96 was slightly superior among ocrelizumab-switchers (94 vs 69%). No serious adverse events were observed in any group. In conclusion, switching from EID-natalizumab to ocrelizumab can be considered as a therapeutic option, particularly in patients with MS at high risk of PML, to mitigate the risks of both PML and disease reactivation.

Amyotrophic lateral sclerosis (ALS), cancer, autoimmunity and metabolic disorders: An unsolved tantalizing challenge.

Amyotrophic lateral sclerosis (ALS) commonly referred to as motor neurone disease, is a neurodegenerative disease of unknown pathogenesis that progresses rapidly and has attracted an increased amount of scholarly interest in recent years. The current conception of amyotrophic lateral sclerosis has transitioned into a more complex theory in which individual genetic risk, ageing and environmental factors interact, leading to disease onset in subjects in whom the sum of these factors reach a determined threshold. Based on this conceptualization, the environmental conditions, particularly those that are potentially modifiable, are becoming increasingly relevant. In this review, the current integrative model of the disease is discussed. In addition, we explore the role of cancer, autoimmunity and metabolic diseases as examples of novel, non-genetic and environmental factors. Together with the potential triggers or perpetuating pathogenic mechanisms along with new insights into potential lines of future research are provided. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc.

Tau/α-synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study.

BACKGROUND: No CSF or plasma biomarker has been validated for diagnosis or progression of PD. OBJECTIVES: To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. METHODS: CSF levels of α-synuclein, amyloid-ß1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1ß, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. RESULTS: CSF levels of α-synuclein, amyloid-ß1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-ß1-42+α-synuclein, and phosphorylated tau/amyloid-ß1-42+α-synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α-synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut-off value of ≤ 0.71). Phosphorylated tau/α-synuclein and phosphorylated tau/amyloid-ß1-42+α-synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin-6 levels were positively correlated with UPDRS-I, -II, and -III scores. CONCLUSIONS: The CSF phosphorylated tau/α-synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin-6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society.

Parkinsonism, cognitive deficit and behavioural disturbance caused by a novel mutation in the polymerase gamma gene.

Polymerase γ (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non-neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 (http://genetics.bwh.hardvard.edu/pph2/) predicted that this change is probably damaging, with a score of 1.0 (0-1).

Nonanaplastic pleomorphic xanthoastrocytoma with meningeal dissemination presenting with bilateral visual loss.

Pleomorphic xanthoastrocytoma (PXA) is a brain neoplasm included in the astrocytic group, exceptionally manifesting with meningeal dissemination. We described a 27-year-old patient presented with acute bilateral visual loss and papilledema with normal brain computed tomography scan, initially mimicking idiopathic intracranial hypertension (IIH). Brain and spinal cord magnetic resonance imaging (MRI) study revealed a subtle area of hyperintensity of the gyri surrounding the left central sulcus, and contrast enhancement of the thoracic leptomeninges. Brain biopsy of the parietal lesion revealed nonanaplastic PXA. Treatment with temozolomide was given. Yearly control MRI demonstrated new brain lesions and marked progression of leptomeningeal spinal enhancement. In spite of this, the patient has remained stable with no new symptoms. Nonanaplastic PXA may present with widespread meningeal dissemination with acute visual loss and papilledema mimicking IIH, and no clinical progression at 3 years.

Progressive multifocal leukoencephalopathy and idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphocytopenia (ICL) is a syndrome described in patients with low counts of CD4 cells and no other causes for immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) have been described in association with this entity. There is no effective treatment for any of them, and the clinical course and outcome are unpredictable. We report on a case of ICL with PML and review the literature, trying to identify the clinical features and the prognosis clues associated to these entities together. A 72-year-old man presented with acute onset gait instability that progressed to a severe cerebellar syndrome with cognitive decline. A cranial MRI showed findings consistent with PML, this diagnosis being confirmed by CSF analyses. Absolute number of CD4+ was 242 cells/µL. An extensive work-up including HIV tests was negative. Ten cases of PML and ICL have previously been reported. Factors contributing to the different outcomes are unknown. Although an effective treatment does not exist for PML, it has been recently demonstrated in vitro that several 5HT2A-receptor antagonists block the JC virus infection. Our patient greatly improved and remains stable 34 months after onset; we describe the potential role of mirtazapine in the treatment of PML.