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Background The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). Objective To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. Methods An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. Results Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values

[This corrects the article on p. e377 in vol. 4, PMID: 28804745.].

To assess the influence of white matter pathology on cortical reorganization, we probed the fronto-parietal attention network in Multiple Sclerosis (MS) patients by combining the Paced Visual Serial Addition Test (PVSAT) with fMRI-guided fiber tractography (FT). During the PVSAT, the control subjects activated the left inferior parietal lobule, superior temporal gyrus, precuneus, precentral gyrus, and medial and middle frontal gyri; while the precuneus and the inferior parietal lobule gyrus bilaterally, the left precentral and angular gyri and the right superior parietal lobule were activated in the MS group. At fMRI-guided FT, the superior longitudinal fasciculus (SLF) was the main white matter tract connecting areas active during the PVSAT. We then identified two subgroups of MS patients according to the SLF mean Fractional Anisotropy, used as indicator of integrity. The activations of the MS patients with a less damaged tract were in the left hemisphere, similarly to controls; while the patients with a more damaged SLF showed bilateral cortical activations. The MS subgroups, however, did not differ in PVSAT performance. This approach could be useful to investigate the relationship between brain structural and functional plastic changes and to identify different MRI endophenotypes related to the same level of cognitive impairment.

The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.

We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.

We report on a patient with delayed carbon monoxide encephalopathy who presented with severe cognitive impairment associated with MRI findings of extensive demyelination of the cerebral white matter after a silent period of three weeks from acute intoxication. Despite the severe signs of structural and functional cerebral impairment in the sub-acute stage, the clinical course was favorable but for residual mild dysfunction of the frontal lobes.

presenting with bulbar-onset amyotrophic lateral sclerosis (ALS), with only minor signs of denervation at the tongue electromyography (EMG), in whom continuous follow-up led to the discovery of a carcinoma of the tongue. We recently observed a 77-year-old man affected by progressive dysarthria, dysphonia, dysphagia and sialorrhea associated with significant weight loss. Neurological examination showed paralysis of the tongue, without atrophy or fasciculations. The other cranial nerves were normal. The proximal muscles of the four limbs and the respiratory muscles were slightly weak. The deep tendon reflexes were increased. A right plantar response in extension was present. Cerebellar and sensory functions were normal. Blood examination showed normocytic–normochromic anaemia and hypoproteinaemia. The CSF was normal. The EMG study showed minor denervation signs on the left anterior tibial muscle, the other examined muscles being normal. The absence of atrophy or fasciculations in the tongue, as in other voluntary muscles, and the lack of reproducible neurophysiological evidence of denervation, prompted us to perform further diagnostic tests. A CT scan of the neck showed an extensive and inoperable tumour involving the base of the tongue and the muscles of the floor of the mouth. At biopsy, an epidermoid carcinoma was diagnosed. Percutaneous endoscopic gastrostomy, tracheotomy and radiotherapy were carried out. Two months later the patient died from severe tongue bleeding. The tongue is the most common site of oral cancer. Symptoms include dysphagia, dysarthria, neck masses, ear pain and weight loss [2]. Diagnosis is often performed in advanced disease stages, because the symptoms are common to many other conditions [3]. In conclusion, our case supports the view that a tongue carcinoma should be considered in the differential diagnosis of bulbar-onset ALS, particularly when clear denervation on EMG or atrophy of the tongue are absent.

Background Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized. Methods Longitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called “Better EDSS Trend (BET)”, was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated. Results Previous EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03). Conclusion Subjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.