Arianna Sartori

The Incidence of Amyotrophic Lateral Sclerosis in Friuli Venezia Giulia, Italy, from 2002 to 2009: A Retrospective Population-Based Study

Background: We conducted a retrospective population-based study to estimate the incidence of amyotrophic lateral sclerosis (ALS) in Friuli Venezia Giulia, Italy, from 2001 to 2009. Methods: Multiple sources were used for case ascertainment: Health databases, archives of the neurology departments and of the regional chapter of the Italian ALS Association. The diagnosis was validated through clinical documentation review. Crude and standardized incidence rates (IRs) per 100,000 person-years were calculated. Results: We identified 262 incident ALS cases, 50.4% men, 4.2% familial. Half of the patients had spinal onset (56.8% in men) and 25.2% bulbar (29% in women). Bulbar onset had a similar frequency in women (31.7%) and men (31.5%) aged 67 or above at diagnosis. The crude IR was 2.72 (95% confidence interval, 95% CI, 2.39-3.05) and the male:female ratio 1.08. The IR peaked in the 65-74 age group, with a second increase in men 85 years and older. The IR standardized to the 2001 Italian population was 2.38 (95% CI 2.13-2.63) and to the 2000 European population 2.58 (95% CI 2.34-2.81). Conclusions: This retrospective study found IRs of ALS in the range of Italian and European prospective population-based registries, suggesting an almost complete case ascertainment.

Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis.

In multiple sclerosis (MS), brain-derived neurotrophic factor (BDNF) provides neuroprotection, but can also promote disease through the maintenance of autoreactive T cells. One aspect that has not been explored yet in MS is related to the opposite functions of BDNF protein isoforms consisting of the pro-BDNF precursor, which has pro-apoptotic effects, and two proteolytic isoforms, the mature BDNF with pro-survival effects and truncated BDNF, with unknown functions. Using ELISA and semi-quantitative Western-blot we determined the relative serum levels of BDNF isoforms in 20 relapsing-remitting MS patients without any disease modifying therapy and 20 age and gender-matched healthy controls and searched for clinical correlates. Total serum BDNF was lower in MS than in HC. We demonstrate that the capture and detection antibodies of the ELISA kit from Promega are able to recognize all three isoforms but with different efficiency. Using Western-blot analysis, we show that the percentage of serum mature BDNF and pro-BDNF with respect to total serum BDNF was significantly decreased, while truncated BDNF was increased. No correlation between BDNF isoform percentage and clinical or demographic features was found. Serum Fas (sFas) was increased. These results support and expand the current hypothesis on the role of BDNF in multiple sclerosis, in that low pro-BDNF and high sFas might result in a failure to limit autoreactive T cells by apoptotic deletion and decreased mature BDNF may not provide enough neuroprotection, while truncated BDNF percent increase could be a compensatory mechanism. Hence, future studies on MS should take into account BDNF proteolytic processing.

Treatment of Fatigue in Multiple Sclerosis Patients: A Neurocognitive Approach

The objective of the study was to treat fatigue in patients with multiple sclerosis (MS) by a neurocognitive rehabilitation program aimed at improving motor planning by using motor imagery (MI). Twenty patients with clinically definite MS complaining of fatigue were treated for five weeks with exercises of neurocognitive rehabilitation twice a week. Patients were evaluated by Fatigue Severity Scale (FSS), Modified Fatigue Impact Scale (MFIS), MSQoL54, Expanded Disability Status Scale (EDSS), and MS Functional Composite (MSFC). After treatment, a decrease in fatigue was detected with both FSS (P = 0.0001) and MFIS (P = 0.0001). MSFC (P = 0.035) and MSQoL54 (P = 0.002) scores improved compared to baseline. At six-month followup, the improvement was confirmed for fatigue (FSS, P = 0.0001; MFIS P = 0.01) and for the physical subscale of MSQoL54 (P = 0.049). No differences in disability scales were found. These results show that neurocognitive rehabilitation, based on MI, could be a strategy to treat fatigue in MS patients.

Teriflunomide: a novel oral treatment for relapsing multiple sclerosis

Introduction: Multiple sclerosis is a disabling chronic inflammatory disease of the CNS. New emerging oral treatments can offer efficacy with higher levels of therapeutic adherence. Teriflunomide is one such oral agent that has recently been approved for the treatment of relapsing multiple sclerosis (RMS). Areas covered: The aim of this review is to describe the pharmacological profile of teriflunomide and review the vast clinical development program that paved the way for its approval, with emphasis on its safety and tolerability. Expert opinion: Teriflunomide is a safe new oral medication for treating RMS. It is effective at reducing relapses, MRI activity and slowing disability progression. It is well tolerated, with mild and transitory side effects. Although teriflunomide is given a pregnancy category ‘X’ by the FDA and an effective contraception is needed, to date, there has been no evidence of teratogenicity in humans and a rapid washout procedure can lead to a virtually complete elimination. Its effectiveness appeared to be at least comparable to that of high-dose IFN-β-1a, and although direct comparisons with other orals are still lacking, its tolerability and encouraging safety data suggest that teriflunomide could be considered an ideal first-line medication for RMS.

The Use of Antidepressant Medication before and after the Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Cohort Study

Background: The prevalent use of antidepressants (ATDs) in patients with Amyotrophic Lateral Sclerosis (ALS) varies across cross-sectional and clinic-based published studies. This population-based cohort study assesses the real-world prevalence of the use of ATDs, its trajectory and the association of incident use with clinical characteristics. Methods: All patients with incident ALS in the Friuli Venezia Giulia region, Italy, from 2002 to 2009, were identified through multiple sources including health databases. Diagnosis was validated through clinical documentation review. ATDs prescriptions from 2000 to 2011 were obtained from regional database. The trajectory was estimated through generalized estimating equations for repeated measures logistic regression and the Hazard ratio (HR) of initiating ATDs through multivariate proportional hazard Cox regression. Results: In this cohort of 261 ALS cases, age-, sex-adjusted prevalence of the use of ATDs was 37.3%, higher than in general population. The trajectory increased by 16% in 1-year period across diagnosis. Age ≤67 years at diagnosis (HR 1.28, 95% CI 0.84-1.95) and bulbar onset (1.43, 95% CI 0.90-2.26) were positively associated with initiating ATDs after diagnosis. Conclusions: More than one-third of patients used ATDs. Depression may occur more frequently than previously reported. Depression may precede motor alterations and be related to both ALS diagnosis and progression.

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study

Objective: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. Methods: We included newly diagnosed patients (2010–2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. Results: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04–1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07–1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). Conclusions: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

Intermittent alien hand syndrome and callosal apraxia in multiple sclerosis: implications for interhemispheric communication.

We report a case of a 47-year-old woman with 35-year history of multiple sclerosis, who showed alien hand signs, a rare behavioural disorder that involves unilateral goal-directed movements that are contrary to the individuals intention. Alien hand syndrome has been described in multiple sclerosis (MS) only occasionally and is generally suggestive of callosal disconnection. The patient presented also with bilateral limb apraxia and left hand agraphia, raising the possibility of cortical dysfunction or disconnection, in addition to corpus callosum and white matter involvement. Her specific pattern of symptoms supports the role of the corpus callosum in interhemispheric communication for complex as well as fine motor activities and may indicate that it can serve as both an inhibitory and excitatory function depending on task demands.

Cerebrospinal Fluid Cytokine Expression Profile in Multiple Sclerosis and Chronic Inflammatory Demyelinating Polyneuropathy

ABSTRACT Background: Cerebrospinal fluid (CSF) analysis in patients with particular neurologic disorders is a powerful tool to evaluate specific central nervous system inflammatory markers for diagnostic needs, because CSF represents the specific immune micro-environment to the central nervous system. Methods: CSF samples from 49 patients with multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and non-inflammatory neurologic disorders (NIND) as controls were submitted to protein expression profiles of 47 inflammatory biomarkers by multiplex Luminex bead assay to investigate possible differences in the inflammatory process for MS and CIDP. Results: Our results showed differences in CSF cytokine levels in MS and CIDP; in particular, IL12 (p40) was significantly highly expressed in MS in comparison with CIDP and NIND, while SDF-1α and SCGF-β were significantly highly expressed in CIDP cohort when compared to MS and NIND. IL-9, IL-13, and IL-17 had higher expression levels in NIND if compared with the other groups. Conclusions: Our study showed that, despite some common pathogenic mechanisms, central and peripheral nervous system demyelinating diseases, such as MS and CIDP, differ in some specific inflammatory soluble proteins in CSF, underlining differences in the immune response involved in those autoimmune diseases.

How far away from having an effective treatment option for progressive multiple sclerosis are we

The availability of numerous disease-modifying drugs for relapsing-remitting (RR) multiple sclerosis (MS) is one of the greatest successes of the last 30 years of neurology history. Unfortunately, this story has a dark side, represented by progressive forms of the disease, still without an effective treatment. A total of 15% of MS patients show a progression form onset, while secondary progression is developed by about 80–90% of RR patients after long-standing disease. Clinical differences between primary progressive (PP) and secondary progressive (SP) forms are well known; nevertheless, these two entities share so many pathological mechanisms and characteristics [1] that seem warranted considering them as part of the same spectrum. The prominence of neurodegeneration over inflammation, with microglial activation, chronic axonal demyelination mediated by oxidative injury, and axonal mitochondrial dysfunction, translates in high disability levels that have deep consequences on patients’ quality of life and give rise to significant familiar, social, and economic burden. It is easy to understand why finding an answer to such a disabling disease represents a priority for scientific community.

Can We Speak of Lack of Habituation in Visual Snow

We read with interest the article by Unal-Cevik et al reporting a case of visual snow (VS) in a patient with a pre-existing migraine with aura (MWA). The authors recorded a subjective improvement of the patient’s VS symptoms after treatment with lamotrigine (LTG) and the effect was objectively assessed by the evaluation of repetitive pattern reversal visual evoked potentials (rVEPs). At baseline, the patient showed a potentiation response, defined as an increase in amplitude of rVEPs between the first and the last block of 100 stimuli, which partially recovered after treatment with LTG. In our opinion, the authors proposed a valid and feasible approach to explore the pathophysiology and therapeutic responsiveness of VS, but we feel that there are some methodological concerns that need to be discussed. First, as the authors correctly stated, “the consequences of cortical hyperexcitability due to comorbid migraine cannot be eliminated,” and this is a crucial point. Indeed the lack of habituation, or even potentiation, is recognized as a characteristic feature of interictal migraine, especially with aura and in VS a high prevalence migraine (30-60%) has already been reported. Therefore, we believe that the potentiation effect on rVEPs that the authors described cannot be unequivocally attributed to VS but rather seems to be related to the underlying MWA. We suggest that this finding should be more prudently confirmed on a larger number of patients, possibly trying to make a distinction between the subgroups of VS with or without comorbid migraine. If we were able to unveil some differences between those two groups we could ascertain whether a state of cortical hyperexcitability is truly VS related or just migraine related. Second, taking in to account the ongoing controversy about the validity of rVEPs habituation paradigms in migraine, we suggest that in a single subject study design the reduction of the potentiation effect after LTG treatment should be interpreted with caution. Changes of few millivolts (mV) between blocks could be explained, for example, by an intrinsic sampling variability, fluctuations in subject’s attention, or concomitant treatments. Perhaps if we were able to demonstrate the restoration of a physiologic habituation response – at a group level – we could have a more solid clue to affirm that a normalization of cortical excitability levels has occurred. Third, LTG has been proven to be effective in the prophylaxis of MWA. Its mechanism of action is still only partially understood and presumably involves the modulation of the glutamatergic transmission, which may be altered in VS as well as in MWA. Some patients with VS reported some improvement of VS after receiving LTG but it is still unclear whether LTG ameliorates VS acting on both VS and migraine pathophysiology or if it has a specific effect on VS. In this specific case, a concomitant effect on MWA should be hypothesized and this observation is supported by the patient’s objective reduction of headache attacks and by the evidence of an increased likelihood of having additional visual symptoms and tinnitus in VS with comorbid migraine. We reaffirm that VS should be considered as a distinct clinical entity although the overlaps with migraine pathophysiology are relevant. Neurophysiological investigations are safe, non-invasive, Abbreviations: LTG, lamotrigine; mV, millivolts; MWA, migraine with aura; rVEPs, repetitive visual evoked potentials; VS, visual snow. Conflict of Interest: The authors declare that there is no conflict of interest.