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Although the diagnosis of Parkinson’s disease (PD) is essentially clinical, the implementation of imaging techniques can improve diagnostic accuracy. While some techniques (e.g. magnetic resonance imaging—MRI, computerized tomography—CT) are used to exclude secondary syndromes, presynaptic dopaminergic imaging including imaging of dopamine transporter (DAT)—can help the Neurologist in the differential diagnosis between neurodegenerative parkinsonian syndromes and parkinsonism without dopamine deficiency. DAT imaging can be useful in cases in which the clinical picture is not univocal, as in case of overlapping clinical features in patients with early disease, atypical syndromes or unsatisfying response to therapy. Currently, (123I)FP-CIT ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) (trade name DaTSCAN) is the only agent approved by international regulatory agencies for this purpose. With the increasing use of this technique, some unexpected findings have been reported, including patients clinically diagnosed with PD with a normal SPECT scan [e.g. Scans Without Evidence of Dopaminergic Deficit (SWEDD)]; PD patients with a greater dopaminergic deficit in the striatum ipsilateral to the clinicallymore affected side [e.g. Scans With Ipsilateral Dopaminergic Deficit (SWIDD)]; as well as some artifacts. Moreover, the neurologist must remember that structural lesions and administration of some drugs might alter the result of DAT imaging. Unexpected findings, artifacts, and misinterpretation of imaging findings can lead to an erroneous diagnosis and inappropriate therapy, neglect of other medical conditions that might explain the clinical picture, and undermine the selection phase in clinical trials. The aim of the present review is to bring clarity on these controversial (and sometimes erroneous) results, in order to informof these possibilities the clinicians requesting a DaTSCAN in clinical practice.

BackgroundHighlighting the relationship between obsessive–compulsive disorder (OCD) and tic disorder (TD), two highly disabling, comorbid, and difficult-to-treat conditions, Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) acknowledged a new “tic-related” specifier for OCD, ie, obsessive–compulsive tic-related disorder (OCTD). As patients with OCTD may frequently show poor treatment response, the aim of this multicenter study was to investigate rates and clinical correlates of response, remission, and treatment resistance in a large multicenter sample of OCD patients with versus without tics.MethodsA sample of 398 patients with a DSM-5 diagnosis of OCD with and without comorbid TD was assessed from 10 different psychiatric departments across Italy. For the purpose of the study, treatment response profiles in the whole sample were analyzed comparing the rates of response, remission, and treatment-resistance as well as related clinical features. Multivariate logistic regressions were performed to identify possible factors associated with treatment response.ResultsThe remission group was associated with later ages of onset of TD and OCD. Moreover, significantly higher rates of psychiatric comorbidities, TD, and lifetime suicidal ideation and attempts emerged in the treatment-resistant group, with larger degrees of perceived worsened quality of life and family involvement.ConclusionsAlthough remission was associated with later ages of OCD and TD onset, specific clinical factors, such as early onset and presence of psychiatric comorbidities and concomitant TD, predicted a worse treatment response with a significant impairment in quality of life for both patients and their caregivers, suggesting a worse profile of treatment response for patients with OCTD.

Objectives: The cervicothoracic junction (CTJ) is a region of the spine submitted to significant mechanical stress. The peculiar anatomical and biomechanical characteristics make posterior surgical stabilization of this area particularly challenging. We present and discuss our surgical series highlighting the specific surgical challenges provided by this region of the spine.Methods: We have analyzed and reported retrospective data from patients who underwent a posterior cervicothoracic instrumentation between 2011 and 2019 at the Neurosurgical Department of the Geneva University Hospitals. We have discussed C7 and Th1 instrumentation techniques, rods design, extension of constructs and spinal navigation.Results: 36 patients were enrolled. We have preferentially used lateral mass (LM) screws in the subaxial spine, pedicle screws (PS) in C7, Th1 and upper thoracic spine. We have found no superiority of 3D navigation techniques over 2D fluoroscopy guidance in PS placement accuracy, probably due to the relatively small case series. Surgical site infection was the most frequent complication, significantly associated with tumor as diagnosis.Conclusions: When technically feasible, PS represent the technique of choice for C7 and Th1 instrumentation although other safe techniques are available. Different rods constructs are described although significant differences in biomechanical stability still need to be clarified. Spinal navigation should be used whenever available even though 2D fluoroscopy is still a safe option. Posterior instrumentation of the CTJ is a challenging procedure but with correct surgical planning and technique it is safe and effective.

Background Coronavirus disease-2019 (COVID-19) pandemic had a great impact over all elective neurosurgical activity and important implications in management of neurosurgical urgencies. During the pandemic, some pediatric hospitals reported their experiences. After the emergency phase of the COVID-19 pandemic, the health care system needs to be reorganized to again manage all nonurgent activities, while ensuring safety of both patients and health care workers. Methods We developed preventive measures to limit any possibility of COVID-19 spread, according to the principles of epidemiologic prevention and suggestions from recent literature. To evaluate the efficacy of these measures, we retrospectively reviewed the neurosurgical activity at our institution from May 4 to July 15, 2020. Results One hundred nineteen patients were admitted to the neurosurgical ward, and 80 surgical procedures were performed. Furthermore, 130 outpatient clinics were scheduled. A total of 258 nasopharyngeal swabs and 249 specific interviews were performed. In our series, no cases of positivity for severe acute respiratory syndrome coronavirus-2 infection were found, and no surgical cases were postponed. Discussion We present the management of the neurosurgical activity after the emergency phase at the Neurosurgical Department of Giannina Gaslini Children's Hospital in Genoa, Italy. Conclusions The Italian health care system is undertaking a process of reorganization of resources, in an attempt to restore all nonurgent activities while ensuring safety. After the emergency phase, we are learning to live together with COVID-19 and, although epidemiologic data are encouraging, we must be prepared for an eventual second peak.

Traumatic brain injury frequently causes an elevation of intracranial pressure (ICP) that could lead to reduction of cerebral perfusion pressure and cause brain ischemia. Invasive ICP monitoring is recommended by international guidelines, in order to reduce the incidence of secondary brain injury; although rare, the complications related to ICP probes could be dependent on the duration of monitoring. The aim of this manuscript is to clarify the appropriate timing for removal and management of invasive ICP monitoring, in order to reduce the risk of related complications and guarantee adequate cerebral autoregulatory control. There is no universal consensus concerning the duration of invasive ICP monitoring and its related complications, although the pertinent literature seems to show that the longer is the monitoring maintenance, the higher is the risk of technical issues. Besides, upon 72 h of normal ICP values or less than 72 h if the first computed tomography scan is normal (none or minimal signs of injury) and the neurological exam is available (allowing to observe variations and possible occurrence of new-onset pathological response), the removal of invasive ICP monitoring can be justified. The availability of non-invasive monitoring systems should be considered to follow up patients’ clinical course after invasive ICP probe removal or for substituting the invasive monitoring in case of contraindication to its placement. Recently, optic nerve sheath diameter and straight sinus systolic flow velocity evaluation through ultrasound methods showed a good correlation with ICP values, demonstrating their potential role in place of invasive monitoring or in the early weaning phase from the invasive ICP monitoring.

Our study investigates the relationship, in the aging population, between vertebral fractures, spinal alignment, and quality of life. Kyphotic fractures were related to more significant disability and impaired spinopelvic alignment. The spinal malalignment was strongly associated with fractures in the thoracolumbar junction vertebrae and the absence of powerful compensatory mechanisms as thoracic hypokyphosis and lower lumbar hyperlordosis. Introduction:In adult spine deformity (ASD), the sagittal imbalance is defined by the deformity in the sagittal plane that causes the need for greater use of muscle strength to maintain an upright static posture or walking. Fragility vertebral fractures (VF) and ASD are frequent causes of spinal morbidity in the elderly. The prevalence of both ASD and VF increases with aging. Although these two clinical conditions insist on the same population, little is known about the interactions between sagittal imbalance and vertebral fracture (VF) deformity. The aim of our work is to examine the associations between vertebral fractures, sagittal alignment, and their impact on the quality of life scores in elderly patients. Methods:A retrospective cohort study of 110 patients of both sexes, from a spine surgery waiting list, with at least one VF with ≥ 5° of kyphosis and a full-standing X-ray. Independent variables:the presence of VF with kyphotic deformity ≥ 10°, fracture level, degree of kyphosis (deformity) of the fracture, number of fractures, spinopelvic angular parameters, demographic parameters, and scales of evaluation of the health-related quality of life. Results:A total of 110 patients with mean age 73.8 ± 5.2, of which 70 women (63%) were included in the study. Subjects with at least one VF ≥ 10° presented greater disability and an overall worse sagittal spinal alignment (no VF10° vs VF10°: TPA 21.30 ± 11.5 vs 26.51 ± 12.6, p = 0.041) and more disability (no VF10° vs VF10°: ODI 41.91 ± 16.9 vs 54.67 ± 15.8, p < 0.001) than patients with less degree of vertebral deformity. Significant compensatory mechanisms involved the thoracic area and the lower lumbar region. Conclusion:Kyphotic VFs were associated with severe alterations of sagittal spine alignment and perceived disability. Subjects with sagittal imbalance have a greater degree of deformity in the thoracolumbar junction area. Thoracic hypokyphosis and lower lumbar hyperlordosis are effective compensatory mechanisms in case of lumbar or thoracic fracture, respectively.

Endoscopic endonasal skull base surgery (EESBS) is a clean-contaminated procedure. Guidelines regarding the antibiotic prophylaxis in EESBS have not been developed yet, and today, there are no universally accepted protocols. In this article, we investigated the efficacy of our new ultra-short antibiotic prophylaxis protocol for EESBS guided by the cultural results of preoperative microbiological nasal swabs. We defined as “nasal swab-related antibiotic protocol” the administration of a first-generation cephalosporin (cefazolin 2 g) in patients whose nasal swabs revealed the presence of normal nasal flora or methicillin-sensitive Staphylococcus aureus (MSSA), and the administration of vancomycin 1 g intravenously in patients whose nasal swabs revealed the presence of methicillin-resistant Staphylococcus aureus (MRSA) or with reported cephalosporin/penicillin allergy. This case-control study included 120 patients who underwent EESBS. The case group included 60 cases who received the “nasal swab-related antibiotic protocol,” while the control group included 60 cases who received the “standard hospital antibiotic protocol” used in neurosurgery (cefazolin 2 g plus metronidazole 500 mg at induction, and 2 g of cefazolin repeated after 180 min). The preoperative microbiological nasal swabs showed normal nasal flora in 42 patients (70%), MSSA in 17 patients (28.3%), and MRSA in 1 patient (1.6%). During the study period, no cases of meningitis or sinusitis occurred in the case group (“nasal swab-related antibiotic protocol”), while two infections (3.3%, 1 sinusitis and 1 meningitis) were reported in the control group (“standard hospital antibiotic protocol”). Mean length of hospitalization was 6.5 days for the case group and 8.5 days in the control group. “Standard hospital antibiotic protocol” is less expensive (range, 2.88–5.42 euros) compared with our new “nasal swab-related antibiotic protocol” (range, 10.02–32.56 euros), but in line with other antibiotic prophylaxis protocols reported in literature. The low complication rates of our case series (0%) is comparable to complication rates reported in literature (1.6% for meningitis and 8% for sinusitis). Compared with other perioperative antibiotic regimens reported in literature, the “nasal swab-related antibiotic protocol” is cheap and at least equally effective. We discuss the rationale on which we based the choice of chemoprophylaxis, the timing, and the length of our regimen. Our study confirmed the safety and efficacy of our easily applicable and low-cost antibiotic prophylaxis protocol.

Objective Neurological symptoms of COVID-19 patients have been recently described. However, no comprehensive data have been reported on pre-existing neurological comorbidities and COVID-19. This study aims at evaluating the prevalence of neurological comorbidities, and their association with COVID-19 severity. Methods We evaluated all consecutive patients admitted to the Emergency Room (ER) of our hospital between the 3rd March and the 14th April 2020, and diagnosed with COVID-19. Data on neurological and non-neurological diseases were extracted, as well as data on demographic characteristics and on severity degree of COVID-19. The prevalence of neurological comorbidities was calculated, and multivariate binary logistic regression analyses were used to estimate the association between neurological diseases and COVID-19 severity. Results We included 344 patients. Neurological comorbidities accounted for 22.4% of cases, with cerebrovascular diseases and cognitive impairment being the most frequent. Neurological comorbidity resulted independently associated with severe COVID-19 (OR 2.305; p = 0.012), as well as male gender (p = 0.001), older age (p = 0.001), neoplastic diseases (p = 0.039), and arterial hypertension (p = 0.045). When neurological comorbidity was associated with non-neurological comorbidities, the OR for severe COVID-19 rose to 7.394 (p = 0.005). Neurological patients, in particular cerebrovascular and cognitively impaired ones, received more respiratory support indication. Conclusion Neurological comorbidities represent a significant determinant of COVID-19 severity, deserving a thorough evaluation since the earliest phases of infection. The vulnerability of patients affected by neurological diseases should suggest a greater attention in targeting this population for proactive viral screening.

Percutaneous vertebroplasty (VTP) is a well-known surgical technique used for pain management and vertebral consolidation in the treatment of osteolytic metastases of the spine. While this indication is proven and commonly accepted, an antitumoral effect of polymethylmethacrylate (PMMA) has been proposed but not yet demonstrated. The aim of our study is to evaluate the evidences of antitumoral effect on anatomopathological examination. We present a small series of pathology findings after VTP for spine metastases that support the lack of antitumoral effect of PMMA. We have retrospectively analyzed three cases of patients treated for en bloc excision of recurrent spine metastases previously submitted elsewhere to VTP on the same levels. We discuss our results with the literature reporting of an antitumoral effect of VTP. In our series, after anatomopathological examination, a cement-induced tumor necrosis was never found. Conversely, a foreign-body reaction around the cement was found, inside vital tumor. These results are consistent with an immune reaction to a foreign body without evidences of an antitumoral effect of PMMA. The antitumoral effect of PMMA should not be taken into account as an indication for VTP in spinal metastases. It is important not to misuse VTP as a therapy aiming at tumor control. Other therapies such as radiotherapy, radiosurgery and open surgery are available for that purpose.

Posterior cranial fossa tumours frequently develop hydrocephalus as first presentation in up to 80% of paediatric patients and 21.4% of adults, although it resolves after tumour removal in 70-90% and 96%, respectively. New onset hydrocephalus is reported in about 2.1% of adult and 10-40% of paediatric patients after posterior fossa surgery. There is no consensus concerning prophylactic external ventricular drainage (EVD) placement that is frequently used before posterior fossa lesion removal, as well in those cases without clear evidence of hydrocephalus. The aim of the study was to define the most correct management for patients who undergo posterior fossa tumour surgery, thus identifying cohorts of patients who are at risk of persistent hydrocephalus prior to surgery. A systematic review of literature has been performed, following PRISMA guidelines. Most of the studies reported CSF shunt only in the presence of hydrocephalus, whereas only a few authors suggested its prophylactic use in the absence of signs of ventricular dilatation. Predictive factors for postoperative hydrocephalus has been identified, including young age ( 3 years), severe symptomatic hydrocephalus at presentation, EVD placement before surgery, FOHR index 0.46 and Evans index 0.4, pseudomeningocele, CSF leak and infection. The use of pre-resection CSF shunt in case of signs and symptoms of hydrocephalus is mandatory, although it resolves in the majority of cases. As reported by several studies included in the present review, we suggest CSF shunt also in case of asymptomatic hydrocephalus, whereas it is not indicated without evidence of ventricular dilatation.

An expert consensus panel convened by the Italian Association for Inherited and Familial Gastrointestinal Tumors (Associazione Italiana per lo Studio della Familiarita ed Ereditarieta dei Tumori Gastrointestinali, AIFEG) reviewed the literature and agreed on a number of position statements regarding the definition and management of polyposis coli without an identified pathogenic mutation on the APC or MUTYH genes, defined in the document as NAMP (non-APC/MUTYH polyposis).

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.

Aims heart failure (HF) and coronary artery disease (CAD) are independent predictors of death in patients with COVID-19. The adverse prognostic impact of the combination of HF and CAD in these patients is unclear. Methods and results we analysed data from 954 consecutive patients hospitalized for SARS-CoV-2 in five Italian Hospitals from February 23 to May 22, 2020. The study was a systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the outcome measure. Mean duration of hospitalization was 33 days. Mortality was 11% in the total population and 7.4% in the group without evidence of HF or CAD (reference group). Mortality was 11.6% in the group with CAD and without HF (odds ratio [OR]: 1.6, p = 0.120), 15.5% in the group with HF and without CAD (OR: 2.3, p = 0.032), and 35.6% in the group with CAD and HF (OR: 6.9, p, Graphical abstract Image, graphical abstract

Spinal aneurysms are rare vascular malformations, commonly associated with spinal AVMs. AVM-associated spinal aneurysms are burdened by significant morbidity. The purpose of our study is to evaluate the best treatment strategy for these uncommon vascular lesions and to report an illustrative case. We reviewed clinical and radiological data of a patient surgically treated at our institution for a spinal AVM with an associated prenidal aneurysm. According to PRISMA guidelines, a systematic literature review has been performed in order to discuss the best management AVM-associated prenidal aneurysms. In the reported case, the aneurysm showed spontaneous regression at follow-up after surgical removal of the AVM. Only 6 articles reported management of spinal prenidal AVM-associated aneurysms. Basing on our experience and data from literature, surgical treatment of the aneurysm may be indicated along with the resection of the AVM if the aneurysm is close to the nidus. Conversely, if the aneurysm is far away from the nidus or in an unfavorable position, resection of the nidus only may lead to aneurysm regression as in the reported case. The treatment strategy for AVM-associated spinal aneurysms should be tailored on the single patient. In presence of large aneurysms that cause mass-effect symptoms, when rupture of the aneurysm is suspected or when treatment of the AVM is not proposable, direct treatment of the aneurysm should be considered. Otherwise, when complete resection of the nidus is performed, the eventually associated unruptured aneurysms located in challenging positions can be safely managed conservatively.

Reduced incidence of stroke during COVID-19 pandemic was sometimes reported. While decrease in stroke incidence and fear of patients to go to the hospitals were sometimes invoked to explain this decrease, reduction in urban pollution was also hypothesized as a possible cause. We investigated statistically the incidence of ischemic and hemorrhagic stroke, and of transient ischemic attacks, at a large Italian tertiary stroke center during the pandemic. We analyzed statistically the number of transient ischemic attacks (TIA), ischemic strokes (IS) and hemorrhagic strokes (HS) between March 8 and May 2, 2020, the peak of the COVID-19 epidemic in Italy, and compared them with the identical period of 2019. We also analyzed the concentration of small particulate matter (PM10) in 2019 and 2020, to see if it could account for modified incidence of strokes or TIA. We found a large, significant drop in TIA (− 51%) during the pandemic compared to the same period of 2019. By contrast, the number of HS was identical, and IS showed a not significant − 24% decrease. PM10 concentration, already low in 2019, did not further decrease in 2020. Patients kept seeking hospital care when experiencing permanent neurological symptoms (stroke), but they tended not go to the hospital when their symptoms were transient (TIA). The fact that we did not observe a significant decrease in strokes may be explained by the fact that in our city the concentration of small particulate matter did not change compared to 2019.

Benefits of pulmonary rehabilitation in Interstitial Lung Diseases (ILD) have been reported. The aim of this large multicenter study was to identify the success predictors of pulmonary rehabilitation in a real-life setting.Data of 240 in-patients (110 idiopathic pulmonary fibrosis (IPF), 106 ILD other than IPF and 24 undetermined ILD) undergoing pulmonary rehabilitation in a 10-year period were retrospectively evaluated. Six minute walking distance (6MWT), body weight-walking distance product tests, dyspnoea and arterial blood gases were assessed at admission and discharge. Differences in post rehabilitation changes in outcome measures as function of baseline characteristics were evaluated.After rehabilitation, patients showed improvements in all outcome measures (p 0.05), regardless of the underlying diagnosis or disease severity. Patients needing oxygen therapy at rest showed reduced benefits. Baseline 6MWD inversely correlated with its changes at discharge. Non-significant greater benefits after rehabilitation were found in IPF patients under antifibrotic therapy. In a subset of 50 patients assessed on average 10.3 ± 3.5 months after discharge, the benefits in 6MWD were not maintained (312.9 ± 139.4, 369.7 ± 122.5 and 310.8 ± 139.6 m at admission, discharge and follow up respectively: p 0.0001).Pulmonary rehabilitation may improve dyspnoea, exercise capacity and fatigue in patients with ILD of different aethiologies and level of severity. The long-term effects need to be established.

Background During the Coronavirus-disease-2019 (COVID-19) pandemic emergency, neurosurgeons may have to decide to prioritize treatments to patients with the best chance of survival, as in a war setting triage. We discuss factors that should be taken into account in the perioperative period and neurocritical care management of neurosurgical patients during a pandemic emergency; in particular, we will focus on the decision on whether to operate or not a patient during the COVID-19 pandemic and where and how to provide neurointensive care treatment. Methods A multidisciplinary expert panel composed by specialists with direct experience in COVID-19 management discussed and reviewed the criteria that should be taken into account in the decision to operate or not a patient during the COVID-19 pandemic. Results Disease-related factors should be first taken into account in order to precisely know the enemy we are facing. Patient-related factors should be then evaluated to understand the battleground on which we are facing the enemy. After these considerations, we must ascertain costs and expected outcomes of our surgical intervention by evaluation of surgery-related factors. Finally, the last factor that need to be evaluated before surgery is the availability of resources, staff and ward availability for perioperative care in particular. All these considerations will lead to the optimal organization and management of neurosurgical emergencies during pandemic times, taking into account the community and not only the single patient. Conclusions We provided schematic preoperative considerations that we hope will help neurosurgeons to guide their decisions in these challenging times.

Creatine is a key player in heart contraction and energy metabolism. Creatine supplementation (throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine) increases creatine content even in the normal heart, and it is generally safe. In heart failure, creatine and phosphocreatine decrease because of decreased expression of the creatine transporter, and because phosphocreatine degrades to prevent adenosine triphosphate (ATP) exhaustion. This causes decreased contractility reserve of the myocardium and correlates with left ventricular ejection fraction, and it is a predictor of mortality. Thus, there is a strong rationale to supplement with creatine the failing heart. Pending additional trials, creatine supplementation in heart failure may be useful given data showing its effectiveness (1) against specific parameters of heart failure, and (2) against the decrease in muscle strength and endurance of heart failure patients. In heart ischemia, the majority of trials used phosphocreatine, whose mechanism of action is mostly unrelated to changes in the ergogenic creatine-phosphocreatine system. Nevertheless, preliminary data with creatine supplementation are encouraging, and warrant additional studies. Prevention of cardiac toxicity of the chemotherapy compounds anthracyclines is a novel field where creatine supplementation may also be useful. Creatine effectiveness in this case may be because anthracyclines reduce expression of the creatine transporter, and because of the pleiotropic antioxidant properties of creatine. Moreover, creatine may also reduce concomitant muscle damage by anthracyclines.

Simple Summary Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. In up to 15% of patients with BM, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. The aim of this review is to summarize current evidence on the diagnosis and treatment of BM-CUP. Abstract Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. BMs may be the cause of the neurological presenting symptoms in patients with otherwise previously undiagnosed cancer. In up to 15% of patients with BMs, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). CUP has an early and aggressive metastatic spread, poor response to chemotherapy, and poor prognosis. The pathogenesis of CUP seems to be characterized by a specific underlying pro-metastatic signature. The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. Advances in diagnostic tools, molecular characterization, and target therapy have shifted the paradigm in the approach to metastasis from CUP: while earlier studies stressed the importance of finding the primary tumour and deciding on treatment based on the primary diagnosis, most recent studies focus on the importance of identifying targetable molecular markers in the metastasis itself. The aim of this review is to summarize current evidence on BM-CUP, from the diagnosis and pathogenesis to the treatment, with a focus on available studies and ongoing clinical trials.

BackgroundAnticoagulant assumption is a concern in neurosurgical patient that implies a delicate balance between the risk of thromboembolism versus the risk of peri- and postoperative hemorrhage.MethodsWe performed a survey among 129 different neurosurgical departments in Italy to evaluate practice patterns regarding the management of neurosurgical patients taking anticoagulant drugs. Furthermore, we reviewed the available literature, with the aim of providing a comprehensive but practical summary of current recommendations.ResultsOur survey revealed that there is a lack of knowledge, mostly regarding the indication and the strategies of anticoagulant reversal in neurosurgical clinical practice. This may be due a lack of national and international guidelines for the care of anticoagulated neurosurgical patients, along with the fact that coagulation and hemostasis are not simple topics for a neurosurgeon.ConclusionsTo overcome this issue, establishment of hospital-wide policy concerning management of anticoagulated patients and developed in an interdisciplinary manner are strongly recommended.

Gilles de la Tourette syndrome (GTS) is a complex neurodevelopmental disorder characterized by tics and, frequently, psychiatric and behavioral comorbidities. Above all, obsessive compulsive disorder/behavior (OCD/OCB) influences the clinical picture and has a severe impact on quality of life, eventually more than the tics themselves. Deep brain stimulation (DBS) is an effective therapy in selected, refractory cases. Clinical response to DBS may vary according to the clinical picture, comorbidities, and to the anatomical target. This retrospective study compares the results obtained from DBS in the ventralis oralis/centromedian-parascicular nucleus of the thalamus (Voi-Cm/Pf) (41 patients) and antero-medial Globus Pallidus internus (am-GPi) (14 patients), evaluating clinical response over time by means of Yale Global Tic Severity Scale (YGTSS) and Yale–Brown Obsessive-Compulsive Scale (YBOCS) scores over a period of 48 months. A significant and stable improvement in the YGTSS and YBOCS has been obtained in both groups (p < 0.001). There was a significant difference in YBOCS improvement over time between the am-GPi group and the Voi-Cm/Pf group, indicating a better and faster control of OCD/OCB symptoms in the former group. The ratio of hardware removal was 23% and limited to 13 patients in the Voi-Cm/Pf group. These results confirm that DBS is an effective therapy in treating GTS and suggest that the am-GPi might be superior to Voi-Cm/Pf in alleviating comorbid OCD/OCB.

Arachnoid cysts may present with symptoms deriving from cyst rupture, usually causing intracystic hemorrhage and subdural hematoma or hygroma. Rupture is usually caused by minor trauma, spontaneous rupture is an exceptional event, and 57 cases have been described in literature. We here present and discuss the largest series of spontaneously ruptured middle fossa arachnoid cysts in order to investigate clinical presentation and best treatment available. We report a retrospective series of 17 pediatric patients surgically treated for middle fossa arachnoid cyst with signs of cyst rupture without a history of trauma in the previous 90 days. We describe clinical presentation, treatment, and outcome at follow-up discussing our results with a literature review including all reported cases of spontaneous rupture of middle fossa arachnoid cysts. In our experience patients most frequently presented with subdural hygroma, in literature, a chronic hematoma was most frequently reported. Headache is the most reported symptom at presentation. Neurological deficits and consciousness alterations are rare. Surgical treatment may resolve brain compression only or reduce rupture recurrence risk. Conservative treatment has also been proposed. Different treatments are reported and discussed focusing on indications, contraindications, risks, and expected benefits. We propose, when safely possible, microsurgical cyst fenestration in skull base cisterns as the treatment of choice for these patients as long as it addresses both immediate decompression and risk of rupture recurrence. We report good outcomes and low incidence of complications from our series with a mean postoperative follow-up of 30 months.

Background Homozygous glucocerebrosidase mutations cause Gaucher disease, whereas heterozygous mutations are the most important genetic risk factor for Parkinson's disease (PD). The penetrance of heterozygous glucocerebrosidase mutations for PD is variable (10%-30%), depends on the population studied, and has only been assessed in Gaucher disease or familial PD. The aim of this study was to assess the penetrance of glucocerebrosidase mutations in PD in unselected PD patients. Methods The penetrance of glucocerebrosidase mutations was estimated using the kin-cohort method. Results Data on family history were available for 63 of 123 PD glucocerebrosidase mutation carriers, identified among 2843 unrelated consecutive PD patients. Three hundred eighty-one first-degree relatives were analyzed. The risk of developing PD was 10% at 60 years, 16% at 70 years, and 19% at 80 years. Conclusions The estimated penetrance of glucocerebrosidase mutations in unselected PD patients is higher than that estimated in Gaucher disease cohorts and lower than that estimated in familial PD cohorts. © 2020 International Parkinson and Movement Disorder Society.

Supplemental Digital Content is available in the text., Background and Purpose: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. Methods: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). Results: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71–0.80] P

BACKGROUND AND PURPOSE: Comorbidity of acute ischaemic stroke with Covid-19 is a challenging condition, potentially influencing the decision of whether to administer intravenous thrombolysis (IVT). We aimed to assess the 1-month outcome in ischaemic stroke patients with Covid-19 infection who received IVT alone or before thrombectomy (bridging therapy). METHODS: As a collaboration initiative promoted by the Italian Stroke Organization, all Italian stroke units (n = 190) were contacted and invited to participate in data collection on stroke patients with Covid-19 who received IVT. RESULTS: Seventy-five invited centers agreed to participate. Thirty patients received IVT alone and 17 received bridging therapy between 21 February 2020 and 30 April 2020 in 20 centers (n = 18, Northern Italy; n = 2, Central Italy). At 1 month, 14 (30.4%) patients died and 20 (62.5%) survivors had a modified Rankin Scale (mRS) score of 3 to 5. At 24 to 36 hours, asymptomatic intracerebral hemorrhage (ICH) was reported in eight (17.4%) patients and symptomatic ICH (sICH) in two (4.3%) patients. Causes of death were severe ischaemic stroke (n = 8), a new ischaemic stroke (n = 2), acute respiratory failure (n = 1), acute renal failure (n = 1), acute myocardial infarction (n = 1), and endocarditis (n = 1). In survivors with a 1-month mRS score of 3 to 5, baseline glucose level was higher, whereas endovascular procedure time in cases of bridging therapy was longer. Baseline National Institutes of Health Stroke Scale glucose and creatinine levels were higher in patients who died. CONCLUSIONS: Intravenous thrombolysis for patients with stroke and Covid-19 was not a rare event in the most affected areas by pandemic, and rates of 1-month unfavorable outcomes were high compared to previous data from the pre-Covid-19 literature. However, risk of sICH was not increased.

Persisters form sub-populations of stress-tolerant cells that play a major role in the capacity of biofilms to survive and recover from disturbances such as antibiotic treatments. The mechanisms of persistence are diverse and influenced by environmental conditions, and persister populations are more heterogeneous than formerly suspected. We used computational modeling to assess the impact of three switching strategies between susceptible and persister cells on the capacity of bacterial biofilms to grow, survive and recover from antibiotic treatments. The strategies tested were: (1) constant switches, (2) substrate-dependent switches and (3) antibiotic-dependent switches. We implemented these strategies in an individual-based biofilm model and simulated antibiotic shocks on virtual biofilms. Because of limited available data on switching rates in the literature, nine parameter sets were assessed for each strategy. Substrate and antibiotic-dependent switches allowed high switching rates without affecting the growth of the biofilms. Compared to substrate-dependent switches, constant and antibiotic-dependent switches were associated with higher proportions of persisters in the top of the biofilms, close to the substrate source, which probably confers a competitive advantage within multi-species biofilms. The constant and substrate-dependent strategies need a compromise between limiting the wake-up and death of persisters during treatments and leaving the persister state fast enough to recover quickly after antibiotic-removal. Overall, the simulations gave new insights into the relationships between the dynamics of persister populations in biofilms and their dynamics of growth, survival and recovery when faced with disturbances., Biofilm persistence: Strategies for switching Computer simulations yield useful insights into strategies bacteria in biofilms use to switch into antibiotic-tolerant “persister” states. A diverse range of mechanisms are available to promote the transition into persister forms. The populations of cells in persister states are proving to be more varied than previously thought. Researchers in France, led by Gabriel Carvalho at the Complex Systems Engineering Laboratory in Aubière, modelled different switching strategies that allow biofilms to survive, recover and grow despite antibiotic treatments. Their procedure examines the effect on switching rates of a greater range of variable factors than previous simulation methods. These variables include the concentration and flow patterns of relevant chemical compounds, changing environmental conditions, and the challenge presented by different antibiotics. The results will help research toward understanding and treating a variety of medically significant biofilm infections.

BACKGROUND: Neurological involvement in Coronavirus disease-2019 (COVID-19) is widely recognized. However, the role of pre-existing neurological comorbidities in modulating COVID-19-related mortality still remains unclear. This cohort study evaluates the COVID-19-related case fatality rate (CFR) of patients with pre-existing neurological diseases. METHODS: We retrospectively evaluated all patients consecutively admitted to our hospital with a diagnosis of COVID-19 between March and April 2020. We used a multivariate regression analysis to estimate the association between pre-existing neurological diseases and COVID-19-related mortality. Then, we compared the CFR and survival curves of two cohorts (patients suffering vs. those not suffering from pre-existing neurological disease), matched trough the propensity score (PS). Age and other comorbidities were considered for PS calculation. We applied a 1:1 matching for the entire neurological cohort and, separately, for cerebrovascular, neurodegenerative, and other neurological diseases. RESULTS: Among 332 patients, 75 (22.6%) were affected by pre-existing neurological disease (n = 29 cerebrovascular, n = 26 neurodegenerative, n = 20 others). From the multivariate regression analysis, they resulted with a significant increase of COVID-19-related mortality (OR:2.559; 95%CI 1.181-5.545; p

Discussion about patients' end-of-life (E-o-L) preferences should be part of the routine practice. Using a semi-structured interview with a scenario-based decision, we performed a prospective multicentre study to elicit the patients' E-o-L preferences in very severe chronic obstructive pulmonary disease (COPD). We also checked their ability to retain this information and the respect of their decisions when they die. Forty-three out of ninety-one of the eligible patients completed the study. The choice of E-o-L practice was equally distributed among the three proposed options: endotracheal intubation (ETI), 'ceiling' non-invasive ventilation (NIV), and palliation of symptoms with oxygen and morphine. NIV and ETI were more frequently chosen by patients who already experienced them. ETI preference was also associated with the use of anti-depressant drugs and a low educational level, while a higher educational level and a previous discussion with a pneumologist significantly correlated with the preference for oxygen and morphine. Less than 50% of the patients retained a full comprehension of the options at 24 hours. About half of the patients who died in the follow-up period were not treated according to their wishes. In conclusion, in end-stage COPD more efforts are needed to improve communication, patients' knowledge of the disease and E-o-L practice.

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) is an autosomal recessive disorder affecting steroidogenesis, due to mutations in CYP21A2 (6p21.3). 21OHD-CAH neonatal screening is based on 17-hydroxyprogesterone (17OHP) serum levels, showing high type I error rate and low sensitivity to mild CAH forms. Here, we used an epidemiological approach, which estimates the allelic frequency (q) of an autosomal recessive disorder using the proportion of homozygous patients, the mutational spectrum and the inbreeding coefficient in a sample of affected individuals. We applied this approach to 2 independent Italian cohorts of patients with both clinical and molecular diagnosis of 21OHD-CAH from mainland Italy (N = 240) and Sardinia (N = 53). We inferred q estimates of 2.87% and 1.83%, corresponding to a prevalence of 1/1214 and 1/2986, respectively. CYP21A2 mutational spectra were quite discrepant between the 2 cohorts, with V281L representing 74% of all the mutations detected in Sardinia vs 37% in mainland Italy. These findings provide an updated fine-grained picture of 21OHD-CAH genetic epidemiology in Italy and suggest the need for a screening approach suitable to the detection of the largest number of clinically significant forms of CAH.

Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

Parkinson's disease is a complex neurodegenerative disorder characterized by motor and non-motor symptoms, with neuropsychiatric manifestations among the most frequent non-motor symptoms. Health-related quality of life is a patient-reported outcome that reflects the impact of the disease on physical, mental, and social wellbeing, and on other aspects of patient' life. Although older studies on health-related quality of life in Parkinson's disease mainly investigated the role of the motor impairment, recent research focused on non-motor symptoms has highlighted the critical role that behavioural disturbances due to neuropsychiatric symptoms play in determining health related quality of life. A considerable number of studies have demonstrated the importance of depression as a determinant of health-related quality of life in this population, but less evidence is available regarding the role of other neuropsychiatric symptoms such as anxiety, apathy, psychosis, and impulse control disorders. This narrative review analyses recent literature on this topic, focusing on studies in which neuropsychiatric symptoms were investigated as potential determinants of quality of life using regression techniques, including discussion of the assessment tools used.

Several enzymes are involved in the energy production, becoming a possible target for new anti-cancer drugs. In this paper, we used biochemical and in silico studies to evaluate the effects of two guanidine molecules, (Boc)2 -creatine and metformin, on creatine kinase, an enzyme involved in the regulation of intracellular energy levels. Our results show that both drugs inhibit creatine kinase activity; however, (Boc)2 -creatine displays a competitive inhibition, while metformin acts with a non-competitive mechanism. Moreover, (Boc)2 -creatine is able to inhibit the activity of hexokinase with a non-competitive mechanism. Considering that creatine kinase and hexokinase are involved in energy metabolism, we evaluated the effects of (Boc)2 -creatine and metformin on the ATP/AMP ratio and on cellular proliferation in healthy fibroblasts, human breast cancer cells (MDA-MB-468), a human neuroblastoma cell line (SH-SY5Y), a human Hodgkin lymphoma cell line (KMH2). We found that healthy fibroblasts were only partially affected by (Boc)2 -creatine, while both ATP/AMP ratio and viability of the three cancer cell lines were significantly decreased. By inhibiting both creatine kinase and hexokinase, (Boc)2 -creatine appears as a promising new agent in anticancer treatment. Further research is needed to understand what types of cancer cells are most suitable to treatment by this new compound. J. Cell. Biochem. 118: 2700-2711, 2017. © 2017 Wiley Periodicals, Inc.

Parkinson's disease is a complex neurodegenerative disorder characterized by motor and non-motor symptoms, with neuropsychiatric manifestations among the most frequent non-motor symptoms. Health-related quality of life is a patient-reported outcome that reflects the impact of the disease on physical, mental, and social wellbeing, and on other aspects of patient' life. Although older studies on health-related quality of life in Parkinson's disease mainly investigated the role of the motor impairment, recent research focused on non-motor symptoms has highlighted the critical role that behavioural disturbances due to neuropsychiatric symptoms play in determining health related quality of life. A considerable number of studies have demonstrated the importance of depression as a determinant of health-related quality of life in this population, but less evidence is available regarding the role of other neuropsychiatric symptoms such as anxiety, apathy, psychosis, and impulse control disorders. This narrative review analyses recent literature on this topic, focusing on studies in which neuropsychiatric symptoms were investigated as potential determinants of quality of life using regression techniques, including discussion of the assessment tools used.

Highlights • Creatine is a compound that is critical for energy metabolism of nervous cells. • Creatine absence due to deficit of creatine transporter causes severe brain symptoms. • Creatine crosses BBB and neuronal membrane slowly, and only using its transporter. • Creatine derivatives may cross BBB and neuronal membrane without the transporter. • Creatine derivatives may be a useful strategy in creatine transporter deficiency., Creatine, a compound that is critical for energy metabolism of nervous cells, crosses the blood-brain barrier (BBB) and the neuronal plasma membrane with difficulty, and only using its specific transporter. In the hereditary condition where the creatine transporter is defective (creatine transporter deficiency) there is no creatine in the brain, and administration of creatine is useless lacking the transporter. The disease is severe and incurable. Creatine-derived molecules that could cross BBB and plasma membrane independently of the transporter might be useful to cure this condition. Moreover, such molecules could be useful also in stroke and other brain ischemic conditions. In this paper, we investigated three creatine salts, creatine ascorbate, creatine gluconate and creatine glucose. Of these, creatine glucose was ineffective after transporter block with guanidine acetic acid (GPA) administration. Creatine ascorbate was not superior to creatine in increasing tissue creatine and phosphocreatine content after transporter impairment, however even after such impairment it delayed synaptic failure during anoxia. Finally, creatine gluconate was superior to creatine in increasing tissue content of creatine after transporter block and slowed down PS disappearance during anoxia, an effect that creatine did not have. These findings suggest that coupling creatine to molecules having a specific transporter may be a useful strategy in creatine transporter deficiency. In particular, creatine ascorbate has effects comparable to those of creatine in normal conditions, while being superior to it under conditions of missing or impaired creatine transporter.

Statins prevent cardiovascular diseases, yet their use is limited by the muscle disturbances they cause. Rarely, statin-induced myopathy is autoimmune, but more commonly it is due to direct muscle toxicity. Available evidence suggests that statin-induced creatine deficiency might be a major cause of this toxicity, and that creatine supplementation prevents it. Statins inhibit guanidinoacetate methyl transferase (GAMT), the last enzyme in the synthesis of creatine; thus, they decrease its intracellular content. Such decreased content could cause mitochondrial impairment, since creatine is the final acceptor of the phosphate group of adenosine triphosphate (ATP) at the end of mitochondrial oxidative phosphorylation. Decreased cellular synthesis of ATP would follow. Accordingly, ATP synthesis is decreased in statin-treated cells. In vitro, creatine supplementation prevents the opening of the mitochondrial permeability transition pore that is caused by statins. Clinically, creatine administration prevents statin myopathy in statin-intolerant patients. Additional research is warranted to hopefully confirm these findings. However, creatine is widely used by athletes with no adverse events, and has demonstrated to be safe even in double-blind, placebo-controlled trials of elderly individuals. Thus, it should be trialed, under medical supervision, in patients who cannot assume statin due to the occurrence of muscular symptoms.