Michele Alessandro Cavallo

Brain Interstitial Nociceptin/Orphanin FQ Levels are Elevated in Parkinson's Disease

Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6‐hydroxydopamine‐hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinsons disease. In this study, we investigated whether elevation of N/OFQ expression in 6‐hydroxydopamine‐hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinsons disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (−20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be ∼3.5‐fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinsons disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.

Pallidal stimulation for segmental dystonia: Long term follow up of 11 consecutive patients†

Pallidal stimulation is a convincing and valid alternative for primary generalized dystonia refractory to medical therapy or botulinum toxin. However, the clinical outcome reported in literature is variable most likely because of heterogeneity DBS techniques employed and /or to clinical dystonic pattern of the patients who undergo surgery. In this study, we report the long term follow up of a homogeneous group of eleven subjects affected by segmental dystonia who were treated with bilateral stimulation of the Globus Pallidus pars interna (GPi) from the years 2000 to 2008. All the patients were evaluated, before surgery and at 6‐12‐24‐36 months after the treatment, in accordance with the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS). Our study indicates that DBS promotes an early and significant improvement at 6 months with an even and a better outcome later on. The analysis of specific sub items of the BFMDRS revealed an earlier and striking benefit not only as far as segmental motor function of the limbs but also for the complex cranial functions like face, (eyes and mouth), speech and swallowing, differently from results reported in primary generalized dystonia. Deep Brain Stimulation of GPi should be considered a valid indication for both generalized and segmental dystonia when other therapies appear ineffective.

Bilateral striatal necrosis, dystonia and multiple mitochondrial DNA deletions: case study and effect of deep brain stimulation.

Bilateral striatal necrosis (BSN) is relatively rare and has been related to a wide array of causes, including nuclear and mitochondrial DNA mutations. We report the clinical vignette of a patient with a 37 years‐history of generalized dystonia secondary to BSN associated with multiple mitochondrial DNA deletions of undefined origin. Globus pallidus interna deep brain stimulation produced sustained benefit, with predominant improvements in disability.

Intraventricular versus intravenous colistin for the treatment of extensively drug resistant Acinetobacter baumannii meningitis.

Reports on the safety and efficacy of intraventricularly administered (IVT) colistin for the treatment of Acinetobacter baumannii ventriculomeningitis in adults are limited and no comparative studies of IVT colistin versus intravenous (IV) therapy alone have been published. This study compared outcomes of patients with postneurosurgical ventriculomeningitis caused by extensively drug‐resistant A. baumannii treated with IV colistin or IV plus IVT colistin.

Switching from constant voltage to constant current in deep brain stimulation: A multicenter experience of mixed implants for movement disorders

For many years deep brain stimulation (DBS) devices relied only on voltage‐controlled stimulation (CV), but recently current‐controlled devices have been developed and approved for new implants as well as for replacement of CV devices after battery drain. Constant‐current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant‐voltage with constant‐current DBS devices, in order to verify the clinical efficacy and safety of this procedure.

Evaluation of acute perihematomal regional apparent diffusion coefficient abnormalities by diffusion-weighted imaging.

In this study, we investigated 40 patients (18 male, 22 female; mean age = 64.5 +/- 11.0; GCS = 9 to 14) with acute supratentorial spontaneous intracerebral hemorrhage (SICH) at admission by using a 1-tesla magnetic resonance imaging (MRI) unit equipped for single-shot echo-planar spin-echo isotropic diffusion-weighted imaging (DWI) sequences. All DWI studies were obtained within 48 hours after symptom onset. Regional apparent diffusion coefficient (rADC) values were measured in 3 different regions of interest (ROIs) drawn freehand on the T2-weighted images at b 0 s/mm2 on every section in which hematoma was visible: 1) the perihematomal hyperintense area; 2) 1 cm of normal appearing brain tissue surrounding the perilesional hyperintense rim; 3) an area mirroring the region including the clot and perihematomal hyperintense area placed in the contralateral hemisphere. rADC mean values were higher in perihematomal hyperintense and in contralateral than in normal appearing areas (p < 0.001), with increased rADC mean levels in all regions examined. Our findings show that rADC values indicative of vasogenic edema were present in the perihematomal area and in normal appearing brain tissue located both ipsilateral and contralateral to the hematoma, with lower levels in non-injured areas located in the T2 hyperintense rim around the clot.

Transpars Microscopic Approach for the Treatment of Purely Foraminal Herniated Lumbar Disc: A Clinical, Radiological Two-Center Study.

Study Design. This is a prospective two-center study. Objective. The aim of this study was to assess the safety and efficacy of treating patients with lumbar foraminal disc herniations via a microscopic transpars approach, with a clinical and radiological follow-up evaluation. Summary of Background Data. Purely foraminal lumbar disc herniations comprise about 5% of all lumbar herniated intervertebral discs. Operative management can be technically difficult, and the optimum surgical treatment remains controversial. Methods. From January 2012 to January 2015, 47 patients were prospectively recruited. Patients were followed-up as outpatients at 1 week after discharge, then at 1, 6, and 12 months. A clinical multiparametric evaluation of patients including numeric rating scale (NRS), drugs intake, Macnab criteria, and working days lost was used. Postoperative dynamic x-rays (flexion, extension) were performed in all cases 12 months after surgery. Results. No surgery-related complications occurred. Among the 35 patients who were not retired at the time of the study, 29 patients returned to work and to normal daily activities within 60 days after surgery. Pain evaluation at discharge showed a significant improvement of NRS score, from 8.93 to 1.45 at 12 months. Root palsy significantly improved in all cases already at 1-month follow-up. Drugs intake analysis showed that at 6-month follow-up, no patients used steroids, or opioids, 17 patients used non-steroidal anti-inflammatory drugs when needed, and 29 patients (61.7%) used no drugs for pain relief. No significant variations occurred at 12-month-follow-up. At 12-month follow-up, excellent or good outcome (following Macnab criteria) was achieved in 36 (76.6%) and 8 (17%) patients, respectively. There were no cases of spinal instability at 12-month radiological evaluation. No recurrence occurred at follow-up. Conclusion. Transpars microscopic approach is effective and safe for the treatment of FLDH, but larger studies are needed. Level of Evidence: 3

Brain tumors in eloquent areas: A European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis

Intraoperative mapping and monitoring techniques for eloquent area tumors are routinely used world wide. Very few data are available regarding mapping and monitoring methods and preferences, intraoperative seizures occurrence and perioperative antiepileptic drug management. A questionnaire was sent to 20 European centers with experience in intraoperative mapping or neurophysiological monitoring for the treatment of eloquent area tumors. Fifteen centers returned the completed questionnaires. Data was available on 2098 patients. 863 patients (41.1%) were operated on through awake surgery and intraoperative mapping, while 1235 patients (58.8%) received asleep surgery and intraoperative electrophysiological monitoring or mapping. There was great heterogeneity between centers with some totally AW oriented (up to 100%) and other almost totally ASL oriented (up to 92%) (31% SD). For awake surgery, 79.9% centers preferred an asleep-awake-asleep anesthesia protocol. Only 53.3% of the centers used ECoG or transcutaneous EEG. The incidence of intraoperative seizures varied significantly between centers, ranging from 2.5% to 54% (p < 0.001). It there appears to be a statistically significant link between the mastery of mapping technique and the risk of intraoperative seizures. Moreover, history of preoperative seizures can significantly increase the risk of intraoperative seizures (p < 0.001). Intraoperative seizures occurrence was similar in patients with or without perioperative drugs (12% vs. 12%, p = 0.2). This is the first European survey to assess intraoperative functional mapping and monitoring protocols and the management of peri- and intraoperative seizures. This data can help identify specific aspects that need to be investigated in prospective and controlled studies.

How to avoid trivial mistakes during IPG replacement in patients treated with DBS for movement disorders: technical note from 13-years experience

Purpose: Recent data suggest how adverse events occur more frequently after Implantable Pulse Generator (IPG) replacement than during the deep electrode positioning in patients treated with Deep Brain Stimulation (DBS). For instance, erroneous extension adjustment to change in laterality and inaccurate lead connection represent problems, which strongly affect patients’ outcome. We analyzed our data after 13 years of IPG replacement. Materials and Methods: We treated 107 patients (83 PD and 24 Dystonia) with DBS in 13 years. The Dual Channel IPGs replaced during this period were 91. 25 patients needed more than one replacement, especially among the dystonic population. During surgery, we temporarily marked in all the cases the right extension lead before the disconnection from the exhausted IPG. Good impedances were intraoperatively checked in all the cases. Results: Our surgical technique allowed us to avoid any erroneous change in laterality or abnormal impedances due to a suboptimal connection to the IPG. The mean duration of the operation was 25 min and a quick postoperative restart of DBS was possible in all the cases. Stability of symptoms after IPG replacement was achieved in all the patients, with an accurate clinical management within the first 48–72 postoperative hours. Conclusion: Our surgical and postoperative management demonstrates how to avoid some important adverse events with some easy steps, without any discomfort for the patients in terms of duration of surgery or longer hospitalization. Thus, stability of symptoms after the IPG replacement may be easily guaranteed during the first postoperative period.

Standard of care, controversies and innovations in the medical treatment of Severe Traumatic Brain Injury (STBI)

Severe traumatic brain injury (STBI) is characterized by a primary injury which cannot be reversed and a secondary injury that can be prevented or reversed. Management of STBI patients in intensive care mainly aims at preventing the secondary injury. Treatment aims to: reducing ICP pressure (that can result in an ischemic insult); avoiding hypotension, hyperthermia, or hypoxemia; maintaining a normal electrolytes homeostasis; treating the autonomic dysfunction syndrome, coagulopathies, acute kidney injury and maintaining an adequate nutrition. Many treatment protocols are already well established, while many others are still debated. Moreover, new frontiers in STBI management are represented by the neurovascular regeneration and neurorestoration which are showing very promising results even if most of them still need a clinical validation. In this paper we review standard of care, controversies and innovations in the medical treatment of STBI.