Eslicarbazepine acetate as adjunctive treatment in partial-onset epilepsy.

OBJECTIVE: The aim of the study was to assess the clinical response to eslicarbazepine acetate (ESL) as add-on therapy in adult patients with partial-onset epilepsy by means of the time-to-baseline seizure count method. METHODS: We retrospectively identified consecutive patients with partial-onset seizures, with or without secondary generalization, prescribed to ESL add-on therapy. The primary endpoint was the time-to-baseline monthly seizure count. Subgroup analysis was performed according to carbamazepine (CBZ)/oxcarbazepine (OXC) status (prior vs never use). Secondary outcomes were the rate of treatment-related adverse events (AEs) and the AEs affecting ≥5% of patients. RESULTS: One-hundred and eighteen patients were included. The median time-to-baseline monthly seizure count was 46 (35-101) days in the overall study cohort. The number of concomitant anti-epileptic drugs (AEDs) was associated with the time-to-endpoint (adjusted hazard ratio [adj HR]=2.22, 95% CI 1.18-4.14, P=.013 for two AEDs vs one; adj HR=3.65, 95% CI 1.66-8.06, P=.001 for three or more AEDs vs one). Groupwise, the median times-to-baseline seizure count were 47 (35-97) and 43 (34-103) in patients with prior and never exposure to CBZ/OXC, respectively (P for log-rank test=.807). Adverse events occurred in 53.4% (63 of 118) of patients; the most frequently reported were dizziness (13.6%), somnolence (11.9%), nausea (6.8%), and fatigue (5.1%). CONCLUSIONS: Add-on ESL improved seizure control and was overall well-tolerated in adult patients with partial-onset epilepsy.

The organisation of the acute ischemic stroke management: key notes of the Italian Neurological Society and of the Italian Stroke Organization.

The main aim of acute ischemic stroke treatment is the as much possible prompt, safe and effective arterial recanalisation, in order to restore reperfusion into the ischemic brain area. The procedures obtaining this result are rapidly evolving and in the last years, we observed new evidences that affirmed the therapeutical benefit of the concomitant treatment using endovenous thrombolysis and mechanical thrombectomy in selected patients with ischemic stroke. However, all treatments are time-sensitive and the main limitation for their application is represented by the time. For this reason, the optimisation of the acute stroke management that includes a pre-hospital and an in-hospital phase is essential to reduce the avoidable delay, increasing the number of patients potentially treatable. The purpose of this document is to define the main elements and to suggest the principal key points constituting the optimal pathway of stroke management in Italian care settings, in line with the recommendations coming from the current national and international guidelines.

Diagnostic delay and prognosis in primary central nervous system lymphoma compared with glioblastoma multiforme.

Glioblastoma multiforme (GBM) and primary central nervous system lymphoma (PCNSL) are malignant cerebral neoplasms associated with poor prognosis. Early diagnosis and subsequent planning of adequate treatment strategy are relevant to improve survival and reduce neurological deficit. Two groups of patients affected by GBM and PCNSL were compared to identify: (1) factors influencing the time necessary to obtain a correct diagnosis; (2) the influence of the interval time from clinical onset to diagnosis on the prognosis. Fifty-six patients (28 PCNSL and 28 GBM, 23 females and 33 males) referred to the same hospital setting were retrospectively evaluated. The mean age at diagnosis was 61 years. The two groups were comparable in terms of age, sex, clinical symptoms at onset and performance status. There was no relevant difference in time span from clinical onset to first neuroimaging examination, while time span from first neuroimaging to final morphological diagnosis was much longer in PCNSL patients (p = 0.008). Multivariate Cox regression analysis, including both PCNSL and GBM cases, showed a significant association of the overall survival with: time to diagnosis (HR 0.06), age at onset (HR 1.04). Our results show a significant diagnostic delay in PCNSL cases. Age at onset of disease and time to diagnosis emerge as clinical factors affecting overall survival in both groups. Stereotactic-guided biopsy should be chosen as routine method to early diagnose PCNSL. The clinical relevance of early diagnosis in GBM and PCNSL needs to be emphasized to maximize the overall survival in both neoplasms.

The neural correlates of road sign knowledge and route learning in semantic dementia and Alzheimer's disease.

BACKGROUND: Although there is a growing body of research on driving and Alzheimer's disease (AD), focal dementias have been understudied. Moreover, driving has never been explored in semantic dementia (SD). METHODS: An experimental battery exploring road sign knowledge and route learning was applied to patients with SD and AD selected in the early-moderate stage of disease and to a group of healthy participants. Neuropsychological data were correlated to cerebral hypometabolism distribution, investigated by means of positron emission tomography. RESULTS: The two dementias showed opposite profiles. Patients with SD showed poor road sign knowledge and normal performance in route learning. By contrast, patients with AD showed low performance in route learning test with preservation of semantic knowledge of road signs. In SD, there was a correlation of semantic knowledge impairment with hypometabolism in the left temporolateral cortex. No correlation between the AD region of interests (ROIs) and the relevant behavioural indices was found, while in the whole-brain analysis there was a significant correlation between route learning and the superior frontal gyrus. DISCUSSION AND CONCLUSIONS: For the first time, driving skills were explored in SD, and it is showed a differential profile from the one detected in AD. We demonstrate that the left anterior temporal cortex is implicated in road sign knowledge, while a distributed cortical network, including the frontal cortex, is likely to process route learning.

Triptan use among hospital workers affected by migraine.

Triptans represent the most specific and effective treatment for migraine attacks. Nevertheless, in clinical practice, they are often underused. Hospital workers, in particular physicians, are expected to be more aware of the correct use of specific drugs, especially for a very common disease such as migraine. Aim of this study was to evaluate whether different hospital workers affected by migraine are able to correctly manage the most suitable therapy for their migraine attacks. During a 1-year period, we submitted hospital employees to a structured interview with a questionnaire to investigate the presence of headache and its characteristics. In particular, in the subpopulation of subjects affected by migraine, we took information regarding their usual treatment for the control of attacks. The type of drug and the category of the working activity were synthesized as two different ordinal variables. Difference in the distribution of the different drug categories was evaluated with Chi squared test. Statistics was performed with SPSS 13.0 for Windows systems. We enrolled 1250 consecutive subjects: 20.3 % of the population (254 patients) was affected by migraine. Triptans use was significantly lower than that of non-steroidal anti-inflammatory drugs. The distribution of the use of the drugs was significantly different (p < 0.0001) at Chi squared test. Among migraineur physicians, only 10.7 % used triptans. Even in this subgroup, we observed a significant difference (p < 0.0001) in the distribution of the use of the drugs at Chi squared test. Our findings show a reduced use of triptans among hospital workers. These data reflect the unsatisfactory dissemination of knowledge regarding the correct management of migraine attacks and the advantages of treatment with triptans. An incorrect therapeutic approach to migraine contributes to the risk of the most important complications, such as drugs abuse or illness chronicization. These findings suggest that an insufficient awareness of migraine-related therapeutic options also involves hospital workers, including physicians.

Natalizumab treatment in multiple sclerosis patients: a multicenter experience in clinical practice in Italy.

We evaluated efficacy of natalizumab in relapsing-remitting multiple sclerosis patients in a clinical practice setting. We report data on the first consecutive 343 patients receiving natalizumab in 12 multiple sclerosis (MS) Italian centers enrolled between April 2007 and November 2010. The main efficacy endpoints were the proportion of patients free from relapses, disease progression, combined clinical activity, defined as presence of relapse or disease progression, from MRI activity, and from any disease activity defined as the absence of any single or combined activity. At the end of follow-up, the cumulative proportion of patients free from relapses was 68%; the proportion of patients free from Expanded Disability Status Scale (EDSS) progression was 93%; the proportion of patients free from combined clinical activity was 65%; the proportion of patients free from MRI activity was 77%; and the proportion of patients free from any disease activity was 53%. Natalizumab was effective in reducing clinical and neuroradiological disease activity. Its effectiveness in clinical practice is higher than that reported in pivotal trials and was maintained over time.

Headache in a population of hospital workers.

Headache prevalence is very high, especially during working life. Hospital workers are expected to be particularly careful with health problems. Few data are available about the dimension of the headache-related problems among hospital workers, including disease awareness and diagnostic delay. 502 subjects employed in our hospital (doctors, nurses, technicians, administrative employees) were enrolled over a 3-month period and submitted to a questionnaire about the presence of headache, its characteristics and time spent from disease onset to diagnosis. We used the ID-migraine test, a validated tool, to obtain a correct migraine diagnosis based on a three-question test. Age and education were collected as continuous variables while the other variables (sex, presence of headache, presence of migraine, diagnosis put by the general practitioners) were encoded as binary. The difference of the distribution of the analyzed variables in tables was evaluated with χ (2) test. The data were analyzed with SPSS 13.0 for Windows systems. In the analyzed population (mean age 40.15 ± 11.0 years; males 60.7 %), 216 patients complained of headache (43.1 %) and 77 (15.4 %) were diagnosed as migraineous at the in-hospital evaluation. Among the 216 cephalalgic patients, the majority (59.7 %, p < 0.0001 at χ (2) test) did not refer to their general practitioner. Of the 77 patients affected by migraine, 55.8 % referred to their general practitioner, but only 27 (35.1 %) received a definite migraine diagnosis. Fifty subjects (64.9 %) were still undiagnosed and unevaluated at the moment of our survey (p < 0.0001 at χ (2) test). Headache prevalence was very high in this population of hospital workers. Diagnostic errors and delays were frequent. Unexpectedly, self-awareness of the headache was very low. Headache, particularly migraine, is a relevant cause of loss of working days and low productivity. Our findings suggest the necessity to program initiatives aimed to raise the awareness of headache in order to improve diagnostic and therapeutic possibilities.

Migraine in health workers: working in a hospital can be considered an advantage?

Migraine is the most common form of headache, and is one of the most diffused pathologies in the world. Moreover, patients often lose years before obtaining a correct diagnosis. The aim of this study was to evaluate whether diagnostic delay differs between hospital workers, in theory more sensible to health problems, and common people. We compared our cohort of patients attending the headache center on which we put a diagnosis of migraine with and without aura with a sample of hospital workers investigated about headache presence and characteristics. Particularly, hospital workers were evaluated by ID-migraine test, a three-question test validated to formulate a migraine diagnosis. Continuous variables (age and diagnostic delay) were compared with t test for independent samples. Dichotomous and categorical variables were compared with Chi squared test. The mean difference between in-hospital workers and outpatients was analyzed with a GLM/multivariate model accounting for age and sex. The difference between the single subcategory of workers affected by migraine was explored with a GLM/multivariate model accounting of age and sex. Five hundred and ninety-nine patients affected by migraine with and without aura were enrolled. Demographical characteristics were comparable in the two study populations. In-hospital workers (99 patients) had a mean longer diagnostic delay (14.89 years; 95 % CI: 7.85-21.93 years) with respect to the outpatients (12.13 years; 95 % CI: 5.37-18.89 years). The difference resulted statistically significant at the multivariate model (p < 0.05). Single subpopulations of in-hospital workers did not have a statistically significant different delay in diagnosing migraine. Diagnostic delay was significantly longer in hospital workers with respect to outpatients. Then, we can conclude that our population of hospital workers did not present a particular attention to their headache, probably because of a tendency to self-treating. Moreover, we did not find differences among different typology of workers, underlining that different job experience and education did not contribute to a best management of headache. More information and informative initiatives are necessary to sensitize people about migraine, especially among hospital workers.

Emergency room access for recurring seizures: when and why.

BACKGROUND AND PURPOSE: To develop a hypothetical model identifying potentially modifiable predictive factors of Emergency Room (ER) visits by patients suffering from drug resistant epilepsy. METHODS: During a 1-year period, all adult drug resistant patients followed by the same epileptologist were recruited after the occurrence of one or more epileptic attacks. They were divided into two groups based on whether they went to the ER after seizures. A prospective comparative analysis of the clinical and social characteristics of the two groups was performed in order to identify independent predictors of ER visits. Logistic regression analysis was used to confirm the potential predictive role of the evaluated variables. RESULTS: Logistic regression analysis confirmed the potential role in predicting ER visits for these variables: foreign nationality, current psychiatric therapy, current antiepileptic drug polytherapy, comorbidities, more than one episode in the same day and changes in usual seizure pattern. A relevant association was also found between the frequency of ER neuroimaging use and the following variables: occurrence of episodes on holidays or weekends, current antiepileptic drug monotherapy, multiple comorbidities and brain injury after seizure. CONCLUSIONS: The present study evaluated factors, some potentially amenable to change, related to drug resistant epileptic patients' ER visits following a seizure. This information may serve to improve the clinical and therapeutic management of patients, decrease the need for urgent care and reduce subsequent patient stress and related costs.

Diagnostic delay in migraine with aura.

Migraine with aura (MWA) is a common headache, characterized by short-lasting neurological signs preceding an headache attack with migraine characteristics. We have recently performed several investigations about time-delay for migraine without aura diagnosis (MWoA). Aim of this study was to compare the time necessary to obtain a correct diagnosis in MWA and MWoA patients. We enrolled 31 consecutive patients affected by MWA and 62 age- and sex-matched patients affected by MWoA. All subjects were submitted to a face-to-face interview about the time-delay from symptoms' onset and a correct migraine typology diagnosis, the number of specialists consulted and the instrumental examinations performed. Independent samples and repeated measures t test, Mann-Whitney U were performed to compare the variables of the cases with the matched controls. No significant differences were found among the collected variables. Diagnostic delay was significantly different (p < 0.05), resulting lower in patients affected by MWA than in those with MWoA. In fact, subjects affected by MWA had a mean diagnostic delay of 6.70 years (SE ± 1.5), while patients affected by MWoA had a mean interval of 10.7 years (SE ± 1.20). Patients affected by MWA present a significant lower delay for the formulation of a correct diagnosis with respect to subjects with MWoA. This could be probably due to the fact that MWA patients develop major alarm reactions related to visual symptoms and look for an earlier appointment with a specialist medical center.

Endovascular treatment of CCSVI in patients with multiple sclerosis: clinical outcome of 462 cases.

Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS.

The real usefulness and indication for migraine diagnosis of neurophysiologic evaluation.

According to IHS criteria, a correct clinical history is fully adequate for a diagnosis of migraine. Patients usually perform many useless instrumental and laboratoristic exams and specialistic evaluations. In particular, electroencephalogram (EEG) is often prescribed as a first-line study in migraine patients. The objective is to analyze the indications of EEG in migraine and to evaluate whether its performance may negatively influence the time necessary to obtain a correct diagnosis. In particular, we compared the effects of EEG performance with those related to neuroradiological examinations in terms of time necessary to obtain a migraine diagnosis. 400 consecutive patients affected by migraine without aura were enrolled. Demographic and clinical data were collected. We used an ordinal regression model considering diagnostic delay as the main outcome and EEG and radiological examinations (in particular brain CT) as predictors. Delay was defined as a time to diagnosis greater than 1-year. Age, sex, number of specialists and examinations were included in the model as covariates. EEG represented the most often performed non-radiologic examination in our sample (20 %). It was associated with a significant risk of diagnostic delay [OR 1.66 (95 % CI 1.65-1.66, p < 0.001)]. An appropriate workup, including CT scan and early referral to a headache center was the most time-saving approach, being associated to the lowest probability of diagnostic delay [OR 0.72 (95 % CI 0.63-0.82, p < 0.001)]. EEG is a frequently prescribed exam in migraine. Our data show that it can contribute to diagnostic delay, highlighting only uncertain and unspecific elements. These data confirm the usefulness of a wide application of IHS guidelines, not recommending this exam for migraine detection.

Applause sign: is it really specific for Parkinsonian disorders? Evidence from cortical dementias.

OBJECTIVE: The applause sign, originally reported as a specific sign of progressive supranuclear palsy (PSP), has recently been found in several parkinsonian disorders. Its nature is still uncertain. It has been interpreted as a motor perseveration or a form of apraxia. The present study aims to: (a) verify the specificity of the applause sign for parkinsonian disorders, examining the presence of the applause sign in cortical dementias which should be error free and (b) clarify the nature of the applause sign (resulting or not from apraxia). METHODS: 77 subjects were included: 10 PSP, 15 frontotemporal dementia (FTD), 29 Alzheimer's disease (AD) and 23 normal controls. The presence of apraxia was an exclusion criterion. All patients underwent a detailed neuropsychological examination, and cognitive performance was correlated to the applause sign. RESULTS: All patient groups showed the applause sign and differed significantly from normal subjects who were error free. No difference was found when comparing PSP with FTD and FTD with AD. AD differed significantly from PSP but they were not error free (31% of patients with AD showed the applause sign). The only correlation with background neuropsychology was found for measures of executive functions. CONCLUSIONS: The presence of the applause sign in cortical dementia does not confirm the specificity of the applause sign for parkinsonian disorders. The applause sign should be interpreted as a sign of frontal lobe dysfunction rather than a form of apraxia, and can likely be detected in any kind of disease which involves frontal lobe structures to some extent.

Platelet amyloid precursor protein isoform expression in Alzheimer's disease: evidence for peripheral marker.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by a progressive cognitive and memory decline. Among peripheral markers of AD, great interest has been focused on the amyloid precursor protein (APP). In this regard, platelets represent an important peripheral source of APP since it has been demonstrated that the three major isoforms, that are constituted of 770, 751 and 695 aa residues, are inserted in the membrane of resting platelets. APP 751 and APP 770 contain a Kunitz-type serine protease inhibitor domain (APP KPI) and APP 695 lacks this domain. To address this issue, we first examined the platelet APP isoform mRNAs prospectively as biomarker for the diagnosis of AD by means of real-time quantitative PCR, and then evaluated the correlation between APP mRNA expression levels and cognitive impairment of enrolled subjects. Differential gene expression measurements in the AD patient group (n=18) revealed a significant up-regulation of APP TOT (1.52-fold), APP KPI (1.32-fold), APP 770 (1.33-fold) and APP 751 (1.26-fold) compared to controls (n=22). Moreover, a statistically significant positive correlation was found between APP mRNA levels (TOT, KPI, 770 and 751) and cognitive impairment. Since AD definitive diagnosis still relies on pathological evaluation at autopsy, the present results are consistent with the hypothesis that platelet APP could be considered a potential reliable peripheral marker for studying AD and could contribute to define a signature for the presence of AD pathology.

The role of instrumental examinations in delayed migraine diagnosis.

Patients affected by migraine without aura very often consult different specialists who, misunderstanding the correct diagnosis, submit them to different instrumental examinations. The objective of the study was to assess if each instrumental examination was really useful for a faster migraine definition, or on the contrary, it increased the time delay for a correct diagnosis. We enrolled 300 consecutive patients referring to our Headache Center with a first diagnosis of migraine without aura and submitted them to a face-to-face interview about time from disease's onset to a correct diagnosis. In each patient, the first instrumental examination performed to specifically investigate migraine-related symptoms was defined. Brain MRI, brain CT, sinus CT, sinus X-rays, cervical spine X-rays and EEG were the most often performed examinations. All the exams, with the exception of brain CT, determined a significant increase of time delay in migraine diagnosis (p < 0.05). Brain CT was significantly associated with a higher probability to obtain a correct diagnosis in less than 1 year. Migraine without aura patients are usually addressed to perform radiological and other instrumental examinations. This attitude may increase the risk of time delay to obtain a correct diagnosis. The performance of a careful clinical history evaluation and neurological examination, with the addition of a brain CT when appropriate, is the best approach for a rapid and correct diagnosis of migraine without aura.

Three years of experience: the Italian registry and safety data update.

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group--Italian Neurological Society.

Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events.

Instrumental investigations and migraine diagnosis.

Migraine diagnosis is based on clinical parameters. Before reaching a correct diagnosis, patients usually consult a large number of specialists and perform unhelpful exams. This represents a significant problem for an optimization of healthy resources. Our aim in this study was to evaluate the relationship between time interval from symptoms' onset to a correct diagnosis and number and type of clinical and instrumental investigations. We considered 180 consecutive patients referred to our Headache Center who obtained the first diagnosis of migraine without aura. Most patients were referred to our center by general practitioners (80%). Previously, about half of patients consulted a specialist not involved in migraine management. In 68% of cases, patients performed radiological and/or laboratory exams. Time from symptom onset to a correct diagnosis of migraine was less than 1 year in only 16.7% of the cases. In 83.3% of patients, the time delay overcame 1 year. In 53.3%, it reached 5 or more years. The time interval to obtain a correct diagnosis significantly influenced the number of specialists consulted and the number of radiological and laboratory investigations performed. Our findings confirm the presence of problems in migraine management. In particular, expensive and unnecessary visits and exams are very often prescribed. This inappropriate procedure could be easily counteracted by a correct application of diagnostic criteria for migraine.

Cognitive and cerebral hemodynamic impairment in scleroderma patients.

BACKGROUND AND PURPOSES: Neurological involvement in systemic sclerosis is unusual despite the possible cerebral localization of vascular lesions. The aim of this study was to evaluate cognitive performances and cerebral vasoreactivity in young scleroderma patients without any signs or symptoms of nervous system involvement. METHODS: Sixteen scleroderma patients and 16 sex- and age-matched healthy subjects without vascular risk factors were included. A neuropsychological assessment for the evaluation of different areas of cognition was performed. For an assessment of cerebrovascular reactivity (CVR), each subject was submitted to hypercapnia with transcranial Doppler ultrasonography using the Breath-Holding Index (BHI). RESULTS: Patients had significantly lower adjusted mean levels of performance with respect to controls in the Modified Card Sorting Test (P < 0.001) and in the Trail Making Test Parts A and B (P < 0.001 and P < 0.05 respectively). Regarding CVR, BHI values were significantly lower in patients with respect to controls: 0.82 +/- 0.44 vs. 1.34 +/- 0.18, P < 0.0001. CONCLUSIONS: These findings show the presence of reduced performances of executive functions in scleroderma patients. The associated alteration of CVR in the absence of other apparent causes of cerebrovascular impairment suggests that cognitive problems may be related to an alteration in cerebral perfusion regulation specifically linked to the disease. Further studies are needed to evaluate whether cognitive changes may be positively influenced by treatments aimed to improve vessels functionality in scleroderma patients.