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Background: Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia. Objective: To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects. Methods: We examined 18 patients with Alzheimer’s disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the “Paratonia Scale”. EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) and discontinuous (linear) movements were applied at 2 different velocities (fast and slow). Results: In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles. Conclusion: Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles.

Clinicians are increasingly recognizing the importance of shared decision-making in complex treatment choices, highlighting the importance of the patient's rationale and motivation for switching therapies. This study aimed to evaluate the association between different modalities of changing multiple sclerosis (MS) treatments, cognitive profile and attitude and preferences of patients concerning treatment choice.This multicenter cross-sectional study was conducted at 28 Italian MS centers in the period between June 2016 and June 2017. We screened all MS patients treated with any DMT, with a treatment compliance of at least 80% of therapy administered during the 3 last months who needed to modify MS therapy because of efficacy, safety or other reasons during a follow-up visit. At the time of switching the symbol digit modalities test (SDMT) and the Control Preference Scale (CPS) were evaluated. According to the CPS, patients were classified as "active" (i.e. who prefer making the medical decision themselves), "collaborative" (i.e. who prefer decisions be made jointly with the physician), or "passive" (i.e. who prefer the physician make the decision).Out of 13,657 patients recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%) patients, 69.6% were female and with mean age 40.6 ± 10.5 years, were enrolled. According to the CPS score evaluation, a significant high percentage of patients (51.1%) were considered collaborative, 74 patients (22.5%) were passive, and 60 (18.2%) patients were active. Stratifying according to CPS results, we found a higher SDMT score among collaborative patients compared to active and passive ones (45.8 ± 12.3 versus 41.0 ± 13.2 versus 41.7 ± 12.8, p 0.05).In this study, the CPS evaluation showed that more than 50% of patients who needed to change therapy chose a "collaborative" role in making treatment decision. Cognitive profile with SDMT seems to correlate with patients' preference on treatment decision, showing better scores in collaborative patients.

Guillain-Barre syndrome (GBS) is often associated with a residual disability. Nonetheless, poor and incomplete studies have been published addressed towards the assessment of importance of physiotherapy (FKT) in the recovery. The aim of the study was to explore the effects of prolonged FKT associated with medical therapy and to evaluate the long-term outcome. A retrospective analysis was carried out on patients with GBS who needed to continue rehabilitation after hospitalization and admitted to the Neurological Department of La Spezia from 2003 to 2017. MRC and GBS-Disability scale (GBS-DS) were performed at the time of greatest clinical disability, after medical therapy, and at the end of the overall FKT. The final outcome evaluation was based on the ability to walk with or without support. ANOVA with Bonferroni post-test were used to compare MRC and GBS-DS. Ninety-six patients were admitted, but only 51 satisfied inclusion criteria. Forty patients performed intensive treatment for an average of 60.95 days, and 31 of them, once discharged, are required to continue FKT as outpatients for a mean period of 96.45 days. The mean value of MRC and GBS-DS post-FKT improved significantly compared with the post-medical therapy. Concerning walking, among the 40 patients who did not walk before therapy, 8 need support after the medical therapy and 4 (11.76%) cannot walk independently at the last follow-up. In conclusion, FKT associated to medical therapy can improve the outcome of the disease, if performed for periods exceeding 6 months.

Treatment related fluctuations (TRFs) in Guillain-Barre Syndrome (GBS) are described as one or more episodes of deterioration manifesting within two months after disease onset and following an initial improvement or stabilisation after treatment. They may be encountered in 8% to 16% of patients, but currently predictive factors of TRF occurrence and severity are poorly known. To this end, we evaluated the frequency and clinical features of TRFs in a cohort of GBS patients admitted to the Neurological unit of Sant'Andrea Hospital (La Spezia, Italy) from January 1st, 2003 to December 31st, 2017. Among the 98 GBS collected patients, five (5.1%) developed a TRF during disease course. Consistently with the literature, the majority of our GBS patients who developed a TRF did not report a preceding diarrhoea, had a predominant proximal weakness and all of them had sensory disturbances at the clinical onset. Interestingly, 80% of our TRF patients manifested since GBS onset an autonomic dysfunction with abnormal sweating and a peculiar 'skin flushing' in face, neck and chest. Two patients developed respiratory insufficiency at the TRF time, and they both died. We would advise to pay attention to GBS patients with particular 'skin flushing' in face, neck and chest and abnormal sweating, because these findings could be a red flag for TRF.

Functional symptoms are currently defined as “physical” disorders that are not attributable to an underlying organic disease and of which a psychogenic origin is assumed. The neurological functional symptoms (paresis, visual disturbance, tremor, etc.) represent an important challenge for the clinician, due to the high prevalence, the difficulties in the differential diagnosis with various common neurological diseases, and the poor treatment outcomes. In the present chapter you will find the main diagnostic and therapeutic issues regarding the neurological evaluation of subjects with functional disorders in emergency.

Spasticity is the velocity-dependent hypertonia frequently encountered in patients affected by Upper Motor Neuron Syndrome. It is due to a tonic stretch reflex, which is evoked in patients at rest. The aim of this study, performed using surface electromyography (EMG), was to investigate stretch reflex excitability in the hamstrings muscles of patients affected by progressive Multiple Sclerosis (MS) and to correlate EMG results with clinical findings. Thirty patients and 20 age-matched healthy controls were investigated. EMG activity was recorded from biceps femoris muscle with the patient at rest. To stretch hamstrings muscles, the patient's leg was manually moved from maximal flexion to maximal extension at 3 different velocities to investigate both phasic and tonic stretch reflex. Only 7 patients were affected by hypertonia of the hamstrings; 4 of them showed muscle contracture. A tonic stretch reflex was present in the vast majority of the recruited patients, whether they presented hypertonia of the hamstrings or not. Tonic stretch reflex is often present in the hamstrings muscles of progressive MS patients without producing increased muscle tone. This "ghost spasticity" is likely to be, for its intrinsic features, an important risk factor for the development of contractures in the hamstrings muscles.

Monitoring the quality of acute ischemic stroke (AIS) management is increasingly important since patient outcome could be improved with better access to evidence-based treatments. In this scenario, the aim of our study was to identify thrombolysis rate, reasons for undertreatment, and factors associated with better outcome. From January to December 2016, individuals diagnosed with AIS at the Policlinic San Martino Hospital in Genoa, Italy, were prospectively included. Severity of stroke, site of occlusion, rate and time related in-hospital management of systemic thrombolysis, and mechanical thrombectomy were recorded. Safety and clinical outcomes were compared between different subgroups. Of 459 AIS patients (57.3% females, mean age 78.1), 111 received i.v. thrombolysis (24.4%) and 50 received mechanical thrombectomy (10.9%). Apart from arrival behind the therapeutic window, which was the first limitation to thrombolysis, the main reason of undertreatment was minor stroke or stroke in rapid improvement. Baseline NIHSS ≥ 8 was associated with unfavorable clinical outcome (mRS > 2) (OR 20.1; 95% CI, 1.1–387.4, p = 0.047). Age older than 80 years (OR 5.0; 95% CI, 1.4–64.1, p = 0.01), baseline NIHSS ≥ 7 (OR 20.1; 95% CI, 1.1–387.4, p = 0.047), and symptomatic intracranial hemorrhage (OR 22.9; 95% CI, 2.0–254.2, p = 0.01) proved independently associated with mortality. i.v. thrombolysis and mechanical thrombectomy rate was higher than that of previous reports. Minor stroke or stroke in rapid improvement was a major reason for exclusion from thrombolysis of eligible patients. Higher NIHSS proved an independent predictor of unfavorable clinical outcome and death. Strategies to avoid in-hospital delays need to be enforced.

Super refractory status epilepticus (SRSE) is a life-threatening condition in which seizures do not respond to third-line anticonvulsant drug therapy. SRSE is associated with high mortality. How often SRSE occurs, what are the risk factors leading to this condition, and what is the effect on clinical outcome of failure to control seizures are poorly defined. Several studies have evaluated magnetic resonance imaging (MRI) findings in status epilepticus (SE), confirming that SE may directly cause selective neuronal necrosis due to excitotoxic mechanisms, as described in clinical case reports and experimental models. The aim of our study is to illustrate, in a case of SRSE, MRI signal changes during time and to describe which cerebral structures are early involved in this difficult clinical condition. We investigated with serial MRI study a patient affected by childhood generalized epilepsy who developed SRSE of unknown etiology during adulthood. MRI scans showed brain signal changes according to progressive electro-clinical worsening, particularly an early involvement of striatum/pallidus. An extended literature exists about transient MRI changes in SE, but not enough about SRSE, because of the difficulties in executing serial MRI studies in patients with such risky condition. MRI findings in SRSE must be investigated with particular care in order to detect early changes in basal ganglia that could suggest severe prognosis.

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Hirayama disease is a rare neurological disease affecting primarily men in the second to third decades. To date there are only few reports from Italy. We report the case of three young basketball players who presented with clinical, electrophysiological and MRI findings suggestive for Hirayama disease. Although the pathophysiology of the disease is still unknown, several hypotheses have been suggested and two of these are the disproportionate growth of cervical spine and cervical cord/roots during adolescence and the chronic traumatism. We think that, in our cases, the height of basketball players combined with the constant stress caused by the sport, could have contributed to the development of the Hirayama disease. With this report we would stress the importance to be careful to consider this pathology in order to avoid misdiagnosis predictive of poor prognosis in young patients.

Objective Spastic dystonia is one of the positive phenomena of the upper motor neuron syndrome (UMNS). It is characterised by the inability to relax a muscle leading to a spontaneous, although stretch-sensitive, tonic contraction. Although spastic dystonia is a recognized cause of muscle hypertonia, its prevalence among hypertonic muscles of stroke subjects has never been investigated. Differently from spasticity, which is an exaggerated stretch reflex, spastic dystonia is viewed as an efferent phenomenon, due to an abnormal central drive to motoneurons. Methods In 23 hemiparetic stroke subjects showing increased muscle tone of wrist flexors, surface EMG was used to investigate the presence of spontaneous, stretch-sensitive EMG activity in flexor carpi radialis. Results Spontaneous, stretch-sensitive EMG activity was found in 17 subjects. In the remaining 6 subjects, no spontaneous EMG activity was found. Conclusions The majority of stroke subjects is affected by spastic dystonia in their hypertonic wrist flexor muscles. Only a minority of subjects is affected by spasticity. Significance To stop spastic dystonia from being the neglected aspect of UMNS, it is essential to link its definition to increased muscle tone, as occurred for spasticity. Recognizing the real phenomena underling muscle hypertonia could improve its management.

Thiamine (vitamin B1) is a cofactor of fundamental enzymes of cell energetic metabolism; its deficiency causes disorders affecting both the peripheral and central nervous system. Previous studies reported low thiamine levels in cerebrospinal fluid and pyruvate dehydrogenase dysfunction in Friedreich ataxia (FRDA). We investigated the effect of long-term treatment with thiamine in FRDA, evaluating changes in neurological symptoms, echocardiographic parameters, and plasma FXN mRNA levels. Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Guillan-Barré Syndrome (GBS) have been reported. The aim of this work is to report the natural history of patients with GBS, both COVID and not-COVID related, hospitalized in Liguria region, during lock down period, in order to assess clinical features of both groups and possible managements pitfalls due to pandemic emergency. Fifteen GBS patients were admitted to the Hospitals of Liguria, from February 15th to May 3rd 2020, six with SARS-CoV-2 infection and nine without infection. In COVID-19 related GBS five patients presented with classical GBS and one with variant. Two patients presented neurologic symptoms during or shortly after the viral syndrome, suggesting the pattern of a para-infectious profile. Multi-organ involvement, delay in the diagnosis, incomplete work up and start of therapy, were registered in 50% of cases with a GBS-Disability scale ≥4 at follow-up evaluation. In not-COVID-19 related GBS, main problem was diagnostic delay. In three patients the first neurological observation took place after a mean of 33,6 days. Moreover, five patients went to emergency room after an average of 30 days since the onset of neurological symptoms because of fear of contagion. In conclusion, not only SARS-CoV-2 infection can cause GBS, but it can also, due to effects of pandemic on the health organization, affect the outcome of patients with not COVID-19 related GBS., Highlights • Covid-19 and GBS. • Diagnostic and therapeutic delay. • Management pitfalls.

Background clinical factors and frequency of disease-modifying therapy (DMT) changes/interruptions in relapsing-remitting multiple sclerosis (RRMS) patients have not been well defined. The aim of this study was to describe reasons of MS treatment modifications in a large cohort of Italian MS patients. Methods this multicenter, cross-sectional non interventional study (SWITCH) conducted at 28 Italian MS centers, screened, by visit/telephone contact between June 2016 and June 2017, all RRMS patients receiving stable DMT treatment and enrolled patients with change in DMT treatment. Results out of 13,657 recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%), met the study criteria and were considered eligible. Among 303 (90.2% of 336) patients switching, the most common reason was “lack of efficacy” (58.4% of 303). Among 30 (8.9%) patients who interrupted treatment temporarily, the most common reason was pregnancy (40.0% of 30). Out of 3 (0.9%) patients who discontinued treatment permanently, 2 (66.7%) had as first reason as “patient decision”. Multivariate analysis showed that EDSS was the only variable with statistically significant effect on changing treatments (r = 8.33; p-value of Type III Sum of Squares = 0.016). Conclusion in our study, 303 (90.2% of eligible patients) switched treatment, 30 (8.9%) interrupted treatment temporarily, and 3 (0.9%) discontinued treatment permanently. Efficacy remains the main driving force behind switching behavior, as the primary aim of treatment is to be disease free or reduce disease activity.

Background. We investigated low-dose aspirin (ASA) efficacy and safety in subjects with silent brain infarcts (SBIs) in preventing new cerebrovascular (CVD) events as well as cognitive impairment.Methods. We included subjects aged ≥45 years, with at least one SBI and no previous CVD. Subjects were followed up to 4 years assessing CVD and SBI incidence as primary endpoint and as secondary endpoints: (a) cardiovascular and adverse events and (b) cognitive impairment.Results. Thirty-six subjects received ASA while 47 were untreated. Primary endpoint occurred in 9 controls (19.1%) versus 2 (5.6%) in the ASA group (p=0.10). Secondary endpoints did not differ in the two groups. Only baseline leukoaraiosis predicts primary [OR 5.4 (95%CI 1.3-22.9, p=0.022)] and secondary endpoint-a [3.2 (95%CI 1.1-9.6, p=0.040)] occurrence.Conclusions. These data show an increase of new CVD events in the untreated group. Despite the study limitations, SBI seems to be a negative prognostic factor and ASA preventive treatment might improve SBI prognosis.EU Clinical trialis registered with EudraCT Number:2005-000996-16; Sponsor Protocol Number: 694/30.06.04.

Background Spasticity and spastic dystonia are two separate phenomena of the upper motor neuron syndrome. Spasticity is clinically defined by velocity-dependent hypertonia and tendon jerk hyperreflexia due to the hyper-excitability of the stretch reflex. Spastic dystonia is the inability to relax a muscle leading to a spontaneous tonic contraction. Both spasticity and spastic dystonia are present in patients who are at rest; however, only patients with spasticity are actually able to kept their muscles relaxed prior to muscle stretch. The idea that has inspired the present work is that also in patients with spastic dystonia the stretch reflex is likely to be hyper-excitable. Therefore, velocity-dependent hypertonia could be mediated not only by spasticity, but also by spastic dystonia. Methods Tonic stretch reflexes in the rectus femoris muscle were evoked in 30 patients with multiple sclerosis showing velocity-dependent hypertonia of leg extensors and the habituation of the reflex was studied. Moreover, the capability of relax the muscle prior to muscle stretch (spastic dystonia) was also investigated. Results A tonic stretch reflex was evoked in all the enrolled patients. 73% of the patients were able to relax their rectus femoris muscle prior to stretch (spasticity). In the overwhelming majority of these patients, the tonic stretch reflex decreased during repeated stretches. In the remaining 27% of the subjects, the muscle was tonically activated prior to muscle stretch (spastic dystonia). In the patients in whom spastic dystonia progressively increased over the subsequent stretches (50% of the subjects with spastic dystonia), the habituation of the reflex was replaced by a progressive reflex facilitation. Discussion This study shows for the first time that velocity-dependent hypertonia can be caused by two distinct phenomena: spasticity and spastic dystonia. The habituation of the tonic stretch reflex, which is a typical feature of spasticity, is replaced by a reflex facilitation in the half of the subject with spastic dystonia. These preliminary findings suggest that differentiating the two types of velocity-dependent muscle hypertonia (spasticity and spastic dystonia) could be clinically relevant.

Background Affective “Theory of Mind” (ToM) is the specific ability to represent own and others' emotional states and feelings. Several studies examined affective ToM ability in patients with Parkinson's disease (PD), using the “Reading the Mind in the Eyes test” (RMET). However, there has been no agreement as to whether or not affective ToM ability is impaired in PD and such discrepancy may be due to the heterogeneous clinical presentation of PD. Affective disturbance has been linked to the akinetic-rigid form of PD and to gait disturbances, like freezing of gait (FOG). Particularly, FOG has been associated with dysfunction in striatum ability of processing affective inputs. Here we hypothesized that the presence of FOG can be associated with impaired affective ToM ability in PD patients. Methods We evaluated ToM by means of RMET and executive functions using the Tower Of London (ToL) test in 29 PD patients (15 with FOG and 14 without FOG) and 19 healthy age-matched subjects. Results Our results showed that affective ToM is abnormal in PD patients, compared to healthy subjects and that it is more impaired in patients with FOG than in patients without FOG. Further, PD patients with FOG performed worse than PD patients without FOG on the ToL test. Conclusion The affective aspects of ToM can be associated to FOG in patients with PD, thus supporting the idea that FOG is caused by a complex interplay between motor, cognitive and affective factors, rather than being a pure motor problem.

Background: Souvenaid™ is a nutraceutical compound thought to positively enhance synaptic function. In line with this mechanism of action, Souvenaid™ has been shown to improve cognitive function in subjects with mild Alzheimer's disease in randomized clinical trials. To date, however, the potential of Souvenaid™ to improve cognitive functioning in subjects with other neurodegenerative conditions also characterized by synaptic loss has not been explored. Objective: To evaluate the impact of Souvenaid™ on executive functions, social cognition and behavioral disturbances in subjects with the behavioral variant of frontotemporal dementia (bv-FTD). Methods: Twenty-six subjects with bv-FTD were enrolled in the study and randomized to Souvenaid™ (125 ml/day) or placebo groups. After 12 weeks, subjects were switched between the two groups. All subjects, blinded to treatment, underwent clinical and cognitive evaluations at enrollment, after 12 weeks and after 24 weeks. Results: Treatment with Souvenaid™ was associated with a significant reduction of behavioral symptoms and an increase in Theory of Mind skills compared to placebo, which both returned to baseline when Souvenaid™ was discontinued. Souvenaid™ did not have an effect on executive functions. Conclusions: Our results provide evidence of the potential of Souvenaid™ therapy for the treatment of behavioral disturbances and social cognition skills in FTD.

The National Institutes of Health Stroke Scale (NIHSS) is able to predict mortality and functional outcome in patients with ischemic stroke. Its role in primary intracerebral hemorrhage (ICH) is not clear. The objective of our study was to investigate whether NIHSS is a reliable instrument of clinical monitoring and correlates with mortality and functional outcome in ICH. One hundred fifty-six consecutive subjects with primary ICH were included. We evaluated NIHSS at admission. The functional state after a 30-day and a 3-month-long follow-up was assessed by the modified Rankin Scale (mRS). Spearman’s rank correlation coefficient analysis was used for statistics. Sensitivity, specificity, positive predictive value, negative predictive value, global accuracy, and ROC curve were computed using the median score 7 as NIHSS cutoff and the score 4 as mRS cutoff. Median NIHSS score at admission was 7 (16–4); the mean (± SD) was 10.82 (± 8.27). Thirty-two patients (20.5%) died within 30 days and other 22 (14.1%) within 3 months. The median mRS score at 3 months was 4 (6–1); the mean (± SD) was 3.38 (± 2.42). We found a statistically significant correlation between initial NIHSS score and mRS score after 30 days (0.74) and 3 months (0.66, p

Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p = 3.81 * 10 − 8) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development.

Affective "Theory of Mind" (ToM) is the specific ability to represent own and others' emotional states and feelings. Previous studies examined affective ToM ability in patients with Huntington's disease (HD), using the "Reading the Mind in the Eyes test" (RMET). Results were consistent in showing difficulties in inferring complex mental states from photographs of people even in the early stage of HD. However, there has been no agreement as to whether or not cognitive impairments in HD population might have contributed to poor performance on the RMET test. The aim of the present study was to assess whether the affective ToM ability was impaired in the mild to moderate stages of Huntington’s disease, and whether there was an association between compromised ToM ability and the presence of cognitive impairment. We evaluated ToM by means of RMET and global cognitive functioning by means of the MoCA questionnaire in 15 HD patients and 15 healthy subjects (HS). Both groups were matched for age and level of education. Our study showed that the ability to judge a person’s mental states from a picture of their eyes was impaired in HD patients compared to normal population. Indeed, HD subjects gave the 34% of correct responses on RMET, whereas healthy control subjects’ percentage of correct responses was 71%. Furthermore, this impairment was not correlated with global cognitive functioning except for the visuospatial task. These results show that RMET might represent a valid instrument to assess affective ToM ability in HD patients in the mild to moderate stages of the disease, independently from their cognitive status. Since it is known that HD patients, in addition to motor symptoms, suffer from cognitive deficits, including memory and executive impairments, it is important to have an instrument which is not influenced by cognitive abilities. It is possible therefore to use RMET to assess important aspects of HD patients such as their ability to recognize others' emotions and feelings even when patients suffer from cognitive decline.

Delirium is an acute neuropsychiatric syndrome, very common in hospitalized people with medical and neurological conditions. The identification of delirium after stroke is not an easy task and validated psychometric instruments are needed to correctly identify it. We decided to verify if (1) formal training in DSM-V criteria is needed to correctly identify post-stroke delirium, (2) if the use of a brief psychometric instrument such as 4AT improves its identification, (3) the applicability of these scales in the stroke setting. In the first phase of this study we retrospectively studied 102 acute stroke patients in Stroke Units of San Martino Hospital (Genova, Italy) to evaluate delirium with clinical criteria, first by a neurologist without a formal training in DSM-V criteria and after training. Then, we enrolled 100 new acute stroke patients who underwent screening for delirium using 4AT scale and DSM-V criteria. In the first phase, DSM-V criteria training significantly increased the ability to capture delirium (5 vs. 15%). In the second phase, the 4AT was used for delirium screening revealing a 52% of cases of delirium, the same observed by the consensus diagnosis of two senior neurologists (that was 50%). In the second phase, the use of 4AT scale allowed to capture post-stroke delirium as well as the consensus diagnosis by two neurologists. The identification of post-stroke delirium is not an easy task and requires both formal training in DSM-V criteria as well as the application of brief scales, such as the 4AT.

In patients treated with botulinum toxin-A (BoNT-A), toxin-directed antibody formation was related to the dosage and frequency of injections, leading to the empirical adoption of minimum time intervals between injections of 3months or longer. However, recent data suggest that low immunogenicity of current BoNT-A preparations could allow more frequent injections. Our hypothesis is that a short time interval between injections may be safe and effective in reducing upper limb spasticity and related disability. IncobotulinumtoxinA was injected under ultrasound guidance in spastic muscles of 11 subjects, who were evaluated just before BoNT-A injection (T0), and 1month (T1), 2months (T2) and 4months (T3) after injecting. At T1, in the case of persistent disability related to spasticity interfering with normal activities, patients received an additional toxin dose. Seven subjects received the additional dose at T1 because of persistent disability; 4 of them had a decrease of disability 1month later (T2). Rethinking the injection scheme for BoNT-A treatment may have a major impact in the management of spasticity and related disability. Future studies with larger sample sizes are warranted to confirm that injection schedules with short time intervals should no longer be discouraged in clinical practice.

Paraneoplastic limbic encephalitis (PLE) associated with Hu antibodies is a rare autoimmune disorder usually characterized by subacute onset of slowly progressive neurocognitive symptoms. Small cell lung carcinoma is the most frequent PLE-associated cancer, which negatively affects the prognosis of the disease. We report on a patient with acute onset of confusional state and disorganized speech. Cerebrospinal fluid analysis and brain MRI temporal lesions corroborated the diagnostic suspects toward infectious or autoimmune encephalitis but testing for onconeural antibodies suggested the alternative diagnosis of PLE, in the absence of cancer (total-body CT and PET were negative). The patient's serum was positive for Hu antibodies, thus leading to a diagnosis of PLE. First-line immunotherapies were ineffective on the neurocognitive symptoms, which improved after rituximab. Six months later, a retropharyngeal peri-jugular mass was histopathologically diagnosed as a metastasis of lung neuroendocrine tumor. Still clinically improved, the patient died from the oncological disease-related complications. Testing for onconeural antibodies should be considered in patients with clinico-radiological features of acute infectious or autoimmune encephalitis.

Wernicke encephalopathy (WE) is a medical emergency caused by thiamine deficiency, characterized by cerebellar ataxia, ophthalmoplegia, and cognitive disturbances that may progress to Korsakoff amnesia. We describe 2 patients with WE who needed high-dose and long-term treatment with thiamine to obtain neurological improvement and recovery.The first patient was a woman diagnosed with non-Hodgkin lymphoma. After a gastrointestinal infection, she developed depression, memory loss, disorientation, behavioral changes, and ataxic paraplegia. Brain magnetic resonance imaging (MRI) showed bilateral alterations in thalamic, frontal, and periaqueductal regions, suggestive of WE. The second patient was a man who lost 10 kg after surgical gastrectomy; he developed diplopia, ophthalmoplegia, cerebellar ataxia, lower limb paresthesias, and amnesia. A brain MRI demonstrated contrast enhancement of mammillary bodies, compatible with WE.The patients were treated with intramuscular (IM) thiamine (1200 mg/d for 2 months and 900 mg/d for a month, respectively) with gradual cognitive and behavioral improvement and brain MRI normalization, while ataxia and oculomotion improved in following months. In both patients, thiamine was gradually reduced to IM 200 mg/d and continued for a year, without clinical relapses.There is no consensus about dosage, frequency, route, and duration of thiamine administration in WE treatment. Based on our cases, we recommend treating patients with WE with higher doses of IM thiamine for a longer time than suggested (900-1200 mg/d for 1-2 months, in our cases) and to gradually reduce dosage after clinical and radiological improvement, maintaining IM 200 mg/d dosage for at least 1 year.

The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.

Understand if cannabinoids (THC:CBD) are useful in reducing post-stroke spasticity using a neurophysiological quantitative measure as primary endpoint. We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double blind placebo-controlled crossover study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographic recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model ANOVA will be used to compare the stretch reflex amplitude between the time points; semi-quantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment). The study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (AIFA) and local Ethics Committee. Data will be made anonymous and uploaded to an open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

Background Apathy is well described in neurodegenerative conditions, however to date there is no evidence of significant isolated apathy in subjects free from other neurological and psychiatric co-morbidites. Identifying isolated apathy in subjects free from neuropsychiatric conditions could contribute to refining current concepts of apathy and reevaluate its nosological classification as an independent clinical syndrome. Methods We assessed apathy and perceived quality of life in a group of 2751 adults (age 19–40 years) free from neuropsychiatric or medical conditions. Subjects with and without elevated apathy were compared on measures of depression, self-efficacy, behavioral inhibition, and behavioral activation. Results Observed prevalence of isolated elevated apathy was 1.45%. Subjects with apathy presented with reduced quality of life and lower behavioral activation compared to apathy-free subjects, while there was no difference between the two groups on measures of depression, self-efficacy, and perceived social skills. Limitations The main limitation of this study is the use of self-report questionnaires. Conclusions Isolated, ecologically-relevant apathy can be found in adults independently from the presence of subclinical depression or of concurrent medical conditions. Apathy screening should be considered in the evaluation of young non-depressed subjects with reduced perceived quality of life.

IntroductionStroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring.Methods and analysisWe will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment).Ethics and disseminationThe study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee ‘Comitato Etico Regionale della Liguria’. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

Patent foramen ovale (PFO) is a common congenital anatomical defect in the general population with a mean prevalence of 20 %. Transcranial Doppler sonography and echocardiography, both with infusion of agitated saline as an echo contrast, have been introduced for the diagnosis of PFO. Transesophageal echocardiography is considered the gold standard. Several studies have suggested an association between cryptogenetic stroke and PFO, but the role of this condition as a risk factor for stroke is still debated. The aims of this prospective multicentre study are the evaluation of PFO prevalence in the whole ischemic stroke population and the identification of a stroke recurrence profile risk in patients with PFO. All consecutive patients admitted for acute ischemic stroke and with a confirmed diagnosis at discharge are eligible cases for the study. Demographic and vascular risk factors are registered. Clinical severity is summarized by the National Institute of Health stroke scale. Echocardiographic and transcranial studies are performed in each patient to detect the presence of PFO. Prevalence of PFO will be calculated with 95 % CIs. Univariate analysis will be performed to detect the correlation of PFO with different registered factors and multivariable analysis with PFO as independent variable. The present study should contribute to better identify the role of PFO in ischemic stroke risk and recurrence-related events. Qualifying findings of the study are represented by the high number of enrolled patients, the prospective methodology of the study and the presence of secondary instrumental endpoints.

BACKGROUND The histopathological hallmarks in Alzheimer's disease (AD) include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. Glycoxidation plays a crucial role in AD pathogenesis, as pentosidine and Ne- carboxymethyl-lysine (CML), were detected in AD hallmarks, and in vivo cerebrospinal fluid (CSF). However, the definitive role of AGEs in the neuropathology of AD is inconclusive. The aim of this preliminary study was to assess the level of pentosidine in CSF of patients affected by neurological disorders, including probable AD, in order to assess the feasibility of AGEs detection in CSF and to explore pentosidine as a potential biomarker in AD. METHODS Twenty-five patients diagnosed with AD (NINCDS ADRDA criteria) and different neurological disorders were enrolled. Diabetic patients were excluded. Pentosidine, CML, amyloid β1-42 were assessed by high performance liquid chromatography (HPLC) by Odetti modified method,and by sandwich ELISA respectively. RESULTS Our data showed the presence of pentosidine in all CSF samples, a significant increase in CSF pentosidine levels with age (p

Mean blood flow velocity (MFV) of the middle cerebral arteries was monitored in 19 healthy, adult, right-handed subjects during the resting phase and the execution of a series of neuropsychological tests: two right/left discrimination tasks, two mental rotation paradigms (the Ratcliff's test and a cube comparison test) and a phonemic fluency task, which was utilised as an internal control. In the group as a whole, the Ratcliff's test was associated with a significant bilateral increase in MFV versus both the resting state (right: p.000001, left: p.000001) and right/left discrimination tasks (task 1: right: p = .003, left: p = .005; task 2: right: p = .001, left: p = .001). The cube comparison in turn produced a significant increase in MFV versus both the baseline conditions (right: p.000001, left: p.000001) and the Ratcliff's test (right: p = .01, left: p = .002). As expected, the fluency task was associated with a significant asymmetric increase in cerebral perfusion (leftright: p = .0001). Increasing task difficulty (right/left discriminationRatcliffs testcube comparison) was paralleled by a roughly proportional rise in MFV values (right: r = .424, p.01; left: r = .331, p = .01). In conclusion, we were able to demonstrate that (1) in addition to the amount of MFV variation due to right/left discrimination (when required), mental rotation per se causes a bihemispheric activation irrespective of the experimental paradigm; (2) the MFV variation is proportional to the difficulty of the tasks.

Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep-wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50mg u.i.d. with sustained release melatonin 10mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study. Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.

Bilateral ophthalmoplegia may be an unusual sign of vertebrobasilar ischemia. We report the cases of two patients (75 and 73 years old), who suddenly developed drowsiness, bilateral ophthalmoplegia with bilateral ptosis and mild right hemiparesis. In both patients, MRI revealed bilateral thalamic and midbrain infarcts, ECG showed the presence of atrial fibrillation and Doppler study of the extracranial and intracranial vertebral arteries found no significant alterations. Ischemia involving the midbrain and thalamic paramedian regions may cause bilateral ophthalmoplegia and consciousness disturbances. In these two cases, the most plausible etiologic mechanism was cardiac embolism, and the prognosis for bilateral ocular palsy was poor.

Contralateral cerebellar hypometabolism (CCH) is a well established remote functional effect of cerebral damage. Because CCH has been reported to be reversible in acute stroke in at least some patients, the value of cerebellar metabolic asymmetry (CbMA; a reflection of the degree of CCH) as a predictor of stroke outcome has been assessed. Measurements of cerebellar oxygen consumption were performed by positron emission tomography (PET) in 16 patients within 5-30 hours of onset of their first ever middle cerebral artery territory stroke, and again 13-56 days later in 12 survivors. The neurological state was quantified at the time of each PET study and at day 60, with both the Mathew and Orgogozo scales. In the early PET study, the CbMAs ranged from around 0% to nearly 50% (individually significant at p < 0.05 in 9/16 patients) but were neither strongly nor consistently correlated with neurological outcome or recovery at day 60. Similarly, the changes in CbMAs from the early to the late PET study were not correlated with the concomitant neurological evolution. At the late PET study, however, there were excellent positive correlations between CbMAs and both neurological status and size of infarction (assessed by CT in the chronic stage). The correlation with neurological status was explained by the correlation with size of infarction. The poor predictive value of CbMAs in the early PET study may be partly because the cerebral metabolic disturbance might still be evolving at this early stage in some cases. Despite this lack of a strong quantitative link between CbMAs at the early PET study and outcome, the outcome was good in all the patients who did not exhibit significant CCH, suggesting that lack of CCH may predict good outcome in acute middle cerebral artery stroke.

This study describes late-onset Alzheimer's disease (LOAD) in the mild cognitive impairment (MCI) stage, debuting with seizures in a 72 year-old woman. Prodromal AD was consistently diagnosed with four among amyloidosis and neurodegeneration biomarkers about 1 year after onset of seizures. Genetic assessment demonstrated apolipoprotein E ε2/ε3 genotype and three intronic single nucleotide substitutions, two in presenilin 1 and one in amyloid-β protein precursor genes. This case of seizures at onset of LOAD with severe signs of brain amyloidosis and neurodegeneration but with just MCI leads to a re-appraisal of the intriguing relationship between AD pathology and neuron excitability in humans.

Our aim was to evaluate the factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease (AD). Five hundred and twenty-four consecutive outpatients at their first diagnostic work-up (age 78.02+/-6.07 years, education 6.62+/-3.48 years, mean MMSE score 20.23+/-4.89) (+/-S.D.) with probable AD (based on DSM-IV and NINCDS-ADRDA criteria) were enrolled in a multicenter, cross-sectional, regional-based study. For the purpose of the present study, the 11 subtests composing the MMSE and the global MMSE score (ranging from 10 to 29, included) were considered. Factor analysis with Varimax rotation method identified two factors that explained about the 85% of total variance. The first factor explained the 65% of variance and mainly included temporal orientation, delayed recall, attention/concentration, and constructional praxia. The second factor explained the 20% of variance and included reading a sentence, writing a sentence, naming, verbal repetition and immediate memory. The first factor was a reliable index of cognitive deterioration along the MMSE score interval between 29 and 10, whereas the second factor was not a suitable marker in this range. The two-factor structure of the MMSE in AD is shown in a large series of patients. The first factor expresses the ability to use new information and is related with working memory. The second factor is related with a more consolidated knowledge, namely verbal abilities, and is essentially useless in mild to moderate AD.