Selective Cerebrospinal Fluid Hypothermia: Bioengineering Development and In Vivo Study of an Intraventricular Cooling Device (V-COOL).

Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (- 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of - 3.0 °C.

Role of aquaporins in hydrocephalus: what do we know and where do we stand? A systematic review.

INTRODUCTION: Glymphatic fluid circulation may be considered the lymphatic system of the brain and the main role of such system seems to be played by aquaporins (AQPs), a family of proteins which regulates water exchange, in particular AQP4 and 1. Alterations of glymphatic fluid circulation through AQPs variations are now emerging as central elements in the pathophysiology of different brain conditions, like hydrocephalus. This systematic review provides an insight about the role of AQPs in hydrocephalus establishment and compensation, investigating their possible role as diagnostic tools or therapeutic targets. METHODS: PubMed database was screened searching for the relevant existing literature in English language published until February 29th 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. RESULTS: A total of 40 articles met the inclusion criteria for our systematic analysis. AQP4 resulted the most studied water channel, followed by AQP1. The changes in cerebrospinal fluid (CSF), brain parenchyma and choroid plexus (CP) in different hydrocephalus type were analyzed. Moreover, important pharmacological interactions regarding AQP and molecules or conditions were discussed. A very interesting result is the general consensus on increase of AQP4 in hydrocephalic patients, unless in patients suffering from idiopathic normal pressure hydrocephalus, where AQP4 shows a tendency in reduction. CONCLUSION: AQP seem to play a central role in the pathophysiology of hydrocephalus and in its compensation mechanisms. Further studies are required to definitively establish their precise roles and their quantitative changes to allow their utilization as diagnostic tools or therapeutic targets.

Cerebral and occipito-atlanto-axial involvement in mucopolysaccharidosis patients: clinical, radiological, and neurosurgical features.

BACKGROUND: Neurosurgical features of mucopolysaccharidosis (MPS) patients mainly involve the presence of cranio-vertebral junction (CVJ) abnormalities and the development of communicating hydrocephalus. CVJ pathology is a critical aspect that severely influences the morbidity and mortality of MPS patients. Hydrocephalus is slowly progressing; it must be differentiated from cerebral atrophy, and rarely requires treatment. The aim of this paper was to review the literature concerning these conditions, highlighting their clinical, radiological, and surgical aspects to provide a practical point of view for clinicians. RESULTS: CVJ involvement may present with cervical pain, unsteady gait, frequent falls, and progressive impairment of autonomous ambulation, an acute tetraplegia even after minor trauma. Magnetic resonance imaging (MRI) of the cervical spine, including active dynamic flexion and extension scans, is the most powerful imaging technique for detecting spinal cord compression at the CVJ in MPS patients. The main radiological features include atlanto-axial subluxation, odontoid hypoplasia, periodontoid soft tissue masses, spinal canal narrowing, and spinal cord compression. Together with MRI, fine-cut computed tomography (CT) scans with coronal and sagittal three-dimensional reconstructions are important diagnostic tools in the preoperative workup thanks to the information gleaned about bone structure conformation and angles. Finally, angio-CT slices are equally useful in preoperative planning, defining vertebral artery position in relation to bony structures. Surgery of the CVJ is proposed both to treat cord compression with MRI signs of myelopathy or as a preventive treatment in patients at high risk of cord damage. Among different surgical options, we always suggest performing decompression and instrumented stabilization. Hydrocephalus may occasionally present clinically with intracranial hypertension symptoms such as headache, vomiting, and high sight impairment. Neurocognitive symptoms may be hidden by the constitutive cognitive impairment. MRI with a study of dynamic cerebrospinal fluid (CSF) flow is helpful to differentiate from ventriculomegaly, which does not require treatment. Ventriculo-peritoneal shunt placement is the gold standard to treat hydrocephalus, although endoscopic third ventriculostomy has recently shown good results in some patients. CONCLUSION: Early recognition of CVJ pathology and hydrocephalus is critical to avoid the development of severe complications. A multidisciplinary approach involving physicians, neuroradiologists, and neurosurgeons is needed to detect such conditions and to select patients eligible for surgery.

Intracerebral hemorrhage in Intensive Care Unit: early prognostication fallacies. A single center retrospective study.

BACKGROUND: Intracerebral hemorrhage (ICH) admitted to Intensive Care is deem of poor prognosis. The aim of this study was to compare observed and predicted 30-day mortality and to evaluate long term functional outcome in a consecutive ICH cohort. METHODS: Retrospective analysis of prospectively collected data of ICH patients managed in a Neuro-ICU from 2012 to 2015. RESULTS: Out of 136 consecutive patients, 34 (25%) had "withholding of life-sustaining treatment" (WLST) order and 102 (75%) received a "full treatment" (FT). WLST cohort: median (IQR): 72 (70-77) years old, Glasgow Coma Scale (GCS) 4 (3-4) at admission, ICH volume 114 cm3 (68-152); all patients died during neuro-ICU recovery, 28 (82%) patients had brain death diagnosis and 15 (54%) of these were organ donors. FT cohort: 67 (51-73) years old, GCS 9 (6-12) at admission, ICH volume 46 (24-90) cm3, neurosurgery for clot removal in 65 (64%) (P<0.05 vs. WLST cohort for each of previously listed variables); 13 (13%) patients died during neuro-ICU recovery, of these 11 (85%) patients had brain death diagnosis and 4 (36%) of them were organ donors. Overall 30-day observed mortality for FT group was 18% (95% CI: 11-26%). Patients with ICH Score 1, 2, 3, 4+ had 0%, 10%, 16% and 26% 30-day mortality, respectively (P<0.01 vs. ICH Score). Full treatment group 180-day mortality was 32% (95% CI: 24-42%). Modified Rankin Scale (mRS) after one year was ≤3 in 35 (35%), i.e. good recovery, and >3 in 64 (65%). Neurosurgery for clot removal was associated with a lower 30 and 180-day mortality (P=0.01 and P=0.03, respectively) and along with GCS at admission it was an independent significant prognostic factor. CONCLUSIONS: Mortality and functional outcome is less severe than predicted in patients with ICH receiving a full medical and/or surgical treatment.

Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies.

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm3 absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI.

High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.

Cerebral collateral flow defines topography and evolution of molecular penumbra in experimental ischemic stroke.

Intracranial collaterals are dynamically recruited after arterial occlusion and are emerging as a strong determinant of tissue outcome in both human and experimental ischemic stroke. The relationship between collateral flow and ischemic penumbra remains largely unexplored in pre-clinical studies. The aim of the present study was to investigate the pattern of collateral flow with regard to penumbral tissue after transient middle cerebral artery (MCA) occlusion in rats. MCA was transiently occluded (90min) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in terms of perfusion deficit and biosignal fluctuation analyses using multi-site laser Doppler monitoring. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of Heat Shock Protein 70kDa (HSP70) immunohistochemistry. Functional deficit and infarct volume were assessed 24h after ischemia induction. The results show that functional performance of intracranial collaterals during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both the cortex and the striatum, as well as with infarct size and functional deficit. Intracranial collateral flow was associated with reduced areas of both molecular penumbra and ischemic core and increased areas of intact tissue in rats subjected to MCA occlusion followed by reperfusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy.

Ganglioglioma of the spinal cord in neurofibromatosis type 1.

The oncologic involvement of the spinal cord in neurofibromatosis type 1 (NF1) is not a typical feature of the disease. Here, we present a case of ganglioglioma of the spinal cord in a child with NF1 and try to define if this tumor can be considered coincidental or not. A 4-year-old boy affected by NF1 was diagnosed with a spinal cord-enhancing tumor extending from C4 to D3, with a disappearance in the T2 MRI sequences of the cerebrospinal fluid signal. The patient underwent a subtotal resection. The pathological exam revealed a ganglioglioma. To the best of our knowledge, only 1 other case of spinal cord ganglioglioma has been described in an NF1 patient. We suggest considering ganglioglioma in the differential diagnosis of an NF1 patient with a spinal cord tumor due to its favorable survival rate, especially in relation to the anatomical and surgical issues of this tumor that do not always entail a gross total resection.

Optimized system for cerebral perfusion monitoring in the rat stroke model of intraluminal middle cerebral artery occlusion.

The translational potential of pre-clinical stroke research depends on the accuracy of experimental modeling. Cerebral perfusion monitoring in animal models of acute ischemic stroke allows to confirm successful arterial occlusion and exclude subarachnoid hemorrhage. Cerebral perfusion monitoring can also be used to study intracranial collateral circulation, which is emerging as a powerful determinant of stroke outcome and a possible therapeutic target. Despite a recognized role of Laser Doppler perfusion monitoring as part of the current guidelines for experimental cerebral ischemia, a number of technical difficulties exist that limit its widespread use. One of the major issues is obtaining a secure and prolonged attachment of a deep-penetration Laser Doppler probe to the animal skull. In this video, we show our optimized system for cerebral perfusion monitoring during transient middle cerebral artery occlusion by intraluminal filament in the rat. We developed in-house a simple method to obtain a custom made holder for twin-fibre (deep-penetration) Laser Doppler probes, which allow multi-site monitoring if needed. A continuous and prolonged monitoring of cerebral perfusion could easily be obtained over the intact skull.

The association of neural axis and craniovertebral junction anomalies with scoliosis in Rubinstein-Taybi syndrome.

OBJECT: Rubinstein-Taybi syndrome (RSTS) is a rare condition with characteristic genetic and clinical features. The presence of variable vertebral and neural axis abnormalities has been reported in the literature. We describe the possible association of multiple different spinal anomalies in these patients. RESULTS: The radiological exams of two RSTS patients (a female and male of 11 and 13 years) have been reviewed. Both patients presented the simultaneous association of craniovertebral junction bony abnormalities (occipito-C1 condyle subluxation and posterior C2-C3 arches fusion), Chiari I malformation, spinal cord syrinx, low-lying conus medullaris, and scoliosis. CONCLUSION: An association of different spinal cord anomalies is possible in RSTS patients and has to be investigated with a comprehensive neuroimaging study in order to address the proper treatment and prevent the development of neurologic deficits.

Hemodynamic monitoring of intracranial collateral flow predicts tissue and functional outcome in experimental ischemic stroke.

Intracranial collaterals provide residual blood flow to penumbral tissue in acute ischemic stroke and contribute to infarct size variability in humans. In the present study, hemodynamic monitoring of the borderzone territory between the leptomeningeal branches of middle cerebral artery and anterior cerebral artery was compared to lateral middle cerebral artery territory, during common carotid artery occlusion and middle cerebral artery occlusion in rats. The functional performance of intracranial collaterals, shown by perfusion deficit in the territory of leptomeningeal branches either during common carotid artery occlusion or middle cerebral artery occlusion, showed significant variability among animals and consistently predicted infarct size and functional deficit. Our findings indicate that leptomeningeal collateral flow is a strong predictor of stroke severity in rats, similarly to humans. Monitoring of collateral blood flow in experimental stroke is essential for reducing variability in neuroprotection studies and accelerating the development of collateral therapeutics.

Anatomical correlates for category-specific naming of living and non-living things.

INTRODUCTION: Selective naming categories impairments for living and non-living things are widely reported in brain damaged patients. Electrostimulation mapping was used to study the possible anatomical segregation of living/non-living categories in a prospective series of patients operated on for tumor removal. MATERIALS AND METHODS: Fifty brain mappings (patients with no language impairment; range: 14-80 years; mean: 48 years; 26 males; 5 left handed) were performed in 46 left and 4 right hemispheres using two linguistically controlled tasks (naming for living and non-living things) during an awake surgery procedure. Fifteen regions and four macro cortical areas were designed to analyze the distribution of the interference sites. RESULTS: Over 761 sites stimulated in the lateral hemispheres, 130 naming interferences sites were detected in small cortical areas (<1cm(2)). High individual variability was observed for living/non-living word retrieval localization and organization with a majority (62%) of shared living/non-living interferences. Specific living (12%) or non-living (26%) interferences were found too. In group analysis, no statistical significant anatomical localization was observed for living items in left lateral hemispheric cortex. A statistical significant representation of interference sites for non-living objects was found (Generalized Estimating Equation methodology, z-test=2.28, p=0.027) in the left posterolateral temporoparietal cortex. No influence of histopathology, gender and age on anatomical localization of naming categories was detected. CONCLUSION: The existence of dedicated neural structures for naming non-living things in the left posterolateral temporoparietal cortex is supported by this study although high individual differences exist in the organization of word categories retrieval.

Cortical visual evoked potentials recorded after optic tract near field stimulation during GPi-DBS in non-cooperative patients.

OBJECT: Neurophysiologic monitoring during deep brain stimulation (DBS) interventions in the globus pallidus internum (Gpi) for the treatment of Parkinson's disease or primary dystonia is generally based upon microelectrode recordings (MER); moreover, MER request sophisticated technology and high level trained personnel for a reliable monitoring. Recordings of cortical visual evoked potentials (CVEPs) obtained after stimulation of the optic tract may be a potential option to MER; since optic tract lies just beneath the best target for Gpi DBS, changes in CVEPs during intraoperative exploration may drive a correct electrode positioning. PATIENTS AND METHODS: Cortical VEPs from optic tract stimulation (OT C-CEPs) have been recorded in seven patients during GPi-DBS for the treatment of Parkinson's disease and primary dystonia under general sedation. OT C-VEPs were obtained after near-field monopolar stimulation of the optic tract; recording electrodes were at the scalp. Cortical responses after optic tract versus standard visual stimulation were compared. RESULTS: After intraoperative near-field OT stimulation a biphasic wave, named N40-P70, was detected in all cases. N40-P70 neither change in morphology nor in latency at different depths, but increased in amplitude approaching the optic tract. The electrode tip was positioned just 1mm above the point where OT-CVEPs showed the larger amplitude. No MERs were obtained in these patients; OT CVEPs were the only method to detect the Gpi before positioning the electrodes. CONCLUSIONS: OT CVEPs seem to be as reliable as MER to detail the optimal target in Gpi surgery: in addition they are less expensive, faster to perform and easier to decode.

Cavum veli interpositi: just an anatomical variant or a potentially symptomatic CSF compartmentalization?

BACKGROUND: The cavum veli interpositi (CVI) usually is a small CSF-containing abnormality of septum pellucidum, asymptomatic and rare after the age of 3 years. When symptomatic, it is large and can be related to psychiatric disorders, syndromic association of mental retardation and seizures or to hydrocephalus. METHODS: This is the first reported case of an otherwise healthy pediatric patient with a large CVI experiencing episodes of hypertonic loss of consciousness unrelated to epileptic, cardiologic or psychiatric causes without signs of chronic increase in intracranial pressure (ICP). RESULTS: Supposing a CSF compartmentalization in the CVI as the cause of acute poussés of ICP due to block of CSF pathways and considering the severity of the symptoms, an endoscopic fenestration was performed with a reduction of cyst dimensions. CONCLUSION: We suggest considering the fenestration of large CVI even in otherwise asymptomatic patients to avoid the risk of CSF compartmentalization with ICP poussés.

Surgical, medical, and hardware adverse events in a series of 141 patients undergoing subthalamic deep brain stimulation for Parkinson disease.

BACKGROUND: Subthalamic deep brain stimulation has proved significant efficacy in the treatment of Parkinson disease. Adverse events, due to surgical and hardware-related complications, must be clearly addressed to properly balance the cost-effectiveness of the therapy. In addition, limited data exists about medical adverse events after surgery. METHODS: One hundred forty-one patients undergoing subthalamic deep brain stimulation for Parkinson disease from 1998 to 2007 were considered. Medical records, operative notes, clinical findings at follow-up and final outcome were accurately recorded to identify surgical- and hardware-related complications, infections and delayed adverse medical events. RESULTS: Five hundred twenty-two surgical procedures were performed, including electrodes positioning and impulse programmable generators implantation and substitutions. Mean follow-up of the patients was 4.6 years (9 months-10 years). Surgical complications were observed in 5.6% of patients, including two hemorrhages (1.4%) and three (2.1%) inabilities to complete the surgical procedure. Medical delayed adverse events affected 1.4% of patients, with a patient having a fatal aspiration pneumonia. Infections were seen in 5.6% of patients; removal of the hardware was necessary in 3.6%. Hardware-adverse events were observed in 7% of patients, generally requiring minor surgery. Direct surgical mortality was 0%; overall mortality was 0.7% and permanent surgical morbidity was 0.7%. CONCLUSIONS: Deep brain stimulation can be regarded as a safe procedure. Mortality and permanent morbidity are very low, and surgical complications are relatively rare. Nevertheless, minor complications are not infrequent; hence the importance of continuous monitoring of the patients during the follow-up period.

Severely symptomatic craniovertebral junction abnormalities in children: long-term reliability of aggressive management.

OBJECTIVES: The treatment of symptomatic cranio-vertebral junction (CVJ) instability in children affected by CVJ abnormalities is a challenge. A series of severely symptomatic children has been reviewed to understand the controversial long-term effectiveness of the aggressive management of CVJ abnormalities, in terms of clinical improvement, spinal stability and growth. METHODS: Three Down syndrome patients, 1 with mucopolysaccharidosis and 1 with os odontoideum (range 3-6 years old) with a CVJ instability determining spinal cord compression with severe neurological deficits (the patients presented at admission a Ranawat III A/III B neurological condition), were consecutively treated at our institution. Medical records, imaging studies, adopted surgical techniques and long-term results were reviewed. Details of the presenting symptoms, clinical and radiological signs were compared to the signs and symptoms at follow-up. RESULTS: The perioperative use of an halo-orthosis, the operative techniques and the timing of rehabilitation were always tailored to the patient's anatomical features. All the patients showed remarkable neurological improvements, along with construct stability and bone fusion without abnormalities of the developing spine. CONCLUSIONS: Considering the effective long-term results, we recommend, even in severely symptomatic children with CVJ abnormalities, a multidisciplinary aggressive tailored treatment of instability with rigid internal fixation.

Anatomical identification of active contacts in subthalamic deep brain stimulation.

BACKGROUND: Subthalamic Deep Brain Stimulation is a valid surgical procedure for the treatment of idiopathic PD, although its precise mechanism of action is still unclear; moreover, there are no conclusive data about the functional anatomy of the human subthalamic region. Identifying the location of active contacts for StnDBS can yield interesting insights on the mechanisms of action of DBS and the different role played by the anatomical structures of the subthalamic region. METHODS: Twenty-five patients operated on for bilateral StnDBS were considered. During the surgical procedure, a complete intraoperative neurophysiological study was obtained by means of semimicrorecordings and stimulations. After surgery, an MRI study confirmed the position of the electrodes; MR images were subsequently superimposed onto a stereotactic atlas by using a dedicated workstation. The coordinates relative to the tip of the electrodes and active contacts were then calculated. RESULTS: Most of the electrode tips are located inside the subthalamus or immediately ventrally to it. Of the active contacts used for chronic stimulation, 96.5% are located in a well-defined anatomical region, which includes subthalamus, zona incerta, and FF. CONCLUSIONS: Our findings seem to suggest that other structures beyond the subthalamus itself play a clinical role in symptoms control after DBS for PD.