Guilherme Lepski

MR AND CT IMAGING IN THE DYKE-DAVIDOFF-MASSON SYNDROME : REPORT OF THREE CASES AND CONTRIBUTION TO PATHOGENESIS AND DIFFERENTIAL DIAGNOSIS

Cerebral hemiatrophy or Dyke-Davidoff-Masson syndrome is a condition characterized by seizures, facial asymmetry, contralateral hemiplegia or hemiparesis, and mental retardation. These findings are due to cerebral injury that may occur early in life or in utero. The radiological features are unilateral loss of cerebral volume and associated compensatory bone alterations in the calvarium, like thickening, hyperpneumatization of the paranasal sinuses and mastoid cells and elevation of the petrous ridge. The authors describe three cases. Classical findings of the syndrome are present in variable degrees according to the extent of the brain injury. Pathogenesis is commented.

Delayed functional maturation of human neuronal progenitor cells in vitro.

INTRODUCTION Differentiation of neuronal progenitor cells (NPCs) in vitro into functional neurons is dependent on a complex cascade of molecular signaling pathways, many of which remain unknown. More specifically, in human NPCs the relationship between the expression of typical neuronal marker proteins and functional properties, such as firing action potential and synaptic transmission, is not well understood. In the present report, the immunocytochemical, morphological and electrophysiological changes that human NPCs undergo during neuronal differentiation in vitro were investigated. METHODS Human NPCs were differentiated toward a neuronal phenotype. The time course of the expression of neuronal markers and morphological cell changes was mapped and passive and active electrophysiological membrane properties assessed, throughout the neuronal maturation process. RESULTS The acquisition of neuronal markers preceded functional physiological maturation by several weeks. Cell input resistance decreased in the first 2 weeks as cells became less sensitive to input current, while cell capacitance progressively increased with continued neuronal process growth. Functional maturation was observed only by the fifth/sixth week, preceded by a marked increase in Na+ and K+ currents. In contrast, electrophysiological maturation of rodent precursor cells was observed at the end of the first week in vitro. Functionally, human neuronal cells became capable of firing action potentials and forming active synaptic contacts. Many features of the firing pattern however remained immature. CONCLUSIONS The results showed that human NPCs develop remarkably slowly and retain immature neuronal features for a prolonged period. The importance of Na-dependent activity for proper neuronal maturation is emphasized.

cAMP promotes the differentiation of neural progenitor cells in vitro via modulation of voltage-gated calcium channels

The molecular mechanisms underlying the differentiation of neural progenitor cells (NPCs) remain poorly understood. In this study we investigated the role of Ca2+ and cAMP (cyclic adenosine monophosphate) in the differentiation of NPCs extracted from the subventricular zone of E14.5 rat embryos. Patch clamp recordings revealed that increasing cAMP-signaling with Forskolin or IBMX (3-isobutyl-1-methylxantine) significantly facilitated neuronal functional maturation. A continuous application of IBMX to the differentiation medium substantially increased the functional expression of voltage-gated Na+ and K+ channels, as well as neuronal firing frequency. Furthermore, we observed an increase in the frequency of spontaneous synaptic currents and in the amplitude of evoked glutamatergic and GABAergic synaptic currents. The most prominent acute effect of applying IBMX was an increase in L-type Ca2+currents. Conversely, blocking L-type channels strongly inhibited dendritic outgrowth and synapse formation even in the presence of IBMX, indicating that voltage-gated Ca2+ influx plays a major role in neuronal differentiation. Finally, we found that nifedipine completely blocks IBMX-induced CREB phosphorylation (cAMP-response-element-binding protein), indicating that the activity of this important transcription factor equally depends on both enhanced cAMP and voltage-gated Ca2+-signaling. Taken together, these data indicate that the up-regulation of voltage-gated L-type Ca2+-channels and early electrical excitability are critical steps in the cAMP-dependent differentiation of SVZ-derived NPCs into functional neurons. To our knowledge, this is the first demonstration of the acute effects of cAMP on voltage-gated Ca+2channels in NPC-derived developing neurons.

Safe Resection of Arteriovenous Malformations in Eloquent Motor Areas Aided by Functional Imaging and Intraoperative Monitoring

BACKGROUND: Arteriovenous malformations (AVMs) proximal to motor cortical areas or motor projection systems are challenging to manage because of the risk of severe sensory and motor impairment. Surgical indication in these cases therefore remains controversial. OBJECTIVE: To propose a standardized approach for centrally situated AVMs based on functional imaging and intraoperative electrophysiological evaluation. METHODS: We conducted a retrospective analysis of 15 patients who underwent surgical treatment for AVMs in motor cortical areas or proximal to motor projections. Preoperative assessment included functional magnetic resonance and 3-dimensional tractography. Operations were performed under continuous electrophysiological monitoring aided by direct brain stimulation. We identified critical bloody supply to the motor areas by temporary occluding the feeding vessels under electrophysiological monitoring. Clinical outcome was evaluated with the modified Rankin Scale. RESULTS: Total resection was achieved in 12 cases, whereas electrophysiology limited total extirpation in 3 cases. A significant reduction of motor evoked potentials by up to 15% of the initial values was associated with good recovery of motor function; in contrast, the disappearance of potentials correlated with long-term impairment. The mean follow-up time was 13 months, and clinical assessments revealed overall functional improvement (P < .05). After surgery, 11 patients were asymptomatic or presented with only minor neurological deficits. CONCLUSION: Surgical resection of AVMs in eloquent motor areas can be considered a safe option for selected cases when performed in conjunction with a detailed functional assessment. Possible selection criteria for surgical treatment are discussed in light of the presented clinical data. ABBREVIATIONS: AVM, arteriovenous malformation DSA, digital subtraction angiography DTI, diffusion tensor imaging fMRI, functional magnetic resonance imaging MEP, motor evoked potential mRS, modified Rankin Scale SEP, somatosensory evoked potential

Intraoperative assistive technologies and extent of resection in glioma surgery: a systematic review of prospective controlled studies

Several studies published to date about glioma surgery have addressed the validity of using novel technologies for intraoperative guidance and potentially improved outcomes. However, most of these reports are limited by questionable methods and/or by their retrospective nature. In this work, we performed a systematic review of the literature to address the impact of intraoperative assistive technologies on the extent of resection (EOR) in glioma surgery, compared to conventional unaided surgery. We were also interested in two secondary outcome variables: functional status and progression-free survival. We primarily used PubMed to search for relevant articles. Studies were deemed eligible for our analysis if they (1) were prospective controlled studies; (2) used EOR as their primary target outcome, assessed by MRI volumetric analysis; and (3) had a homogeneous study population with clear inclusion criteria. Out of 493 publications identified in our initial search, only six matched all selection criteria for qualitative synthesis. Currently, the evidence points to 5-ALA, DTI functional neuronavigation, neurophysiological monitoring, and intraoperative MRI as the best tools for improving EOR in glioma surgery. Our sample and conclusions were limited by the fact that studies varied in terms of population characteristics and in their use of different volumetric analyses. We were also limited by the low number of prospective controlled trials available in the literature. Additional evidence-based high-quality studies assessing cost-effectiveness should be conducted to better determine the benefits of intraoperative assistive technologies in glioma surgery.

Chronic Pain after Spinal Cord Injury: Clinical Characteristics

The clinical characteristics of chronic pain in spinal cord injury patients are controversial. The authors prospectively evaluated 81 patients with chronic pain due to spinal cord lesions. The mean pain intensity according to the visual analogue scale was 9.4. The most common description of pain was a sensation of burning. The initial pain was more severe in patients presenting with myelopathy due to gunshot injuries (p < 0.001). The pain intensity was not associated with the magnitude of the spinal lesion, location of the lesion, occurrence of myofascial pain syndrome or onset of pain. Pain after spinal cord injury was severe, males were more frequently affected and it was more intense when it was the result of gunshot injury. In about 38% of the patients, pharmacological and rehabilitative procedures were effective. Dorsal root entry zone lesion was effective for the treatment of transitional pain in patients with complete section of the spinal cord, spinal cord stimulation was effective for patients with partial lesions of the spinal cord and intrathecal opioid infusion was effective for both conditions.

Iatrogenic Creutzfeldt-Jakob disease following human growth hormone therapy: case report

We report the case of a 41-year-old man with iatrogenic Creutzfeldt-Jakob disease (CJD) acquired after the use of growth hormone (GH) obtained from a number of pituitary glands sourced from autopsy material. The incubation period of the disease (from the midpoint of treatment to the onset of clinical symptoms) was rather long (28 years). Besides the remarkable cerebellar and mental signs, the patient exhibited sleep disturbance (excessive somnolence) from the onset of the symptoms, with striking alteration of the sleep architecture documented by polysomnography. 14-3-3 protein was detected in the CSF, and MRI revealed increased signal intensity bilaterally in the striatum, being most evident in diffusion-weighted (DW-MRI) sequences. This is the second case of iatrogenic CJD associated with the use of GH reported in Brazil.

Combined Spinal Cord and Peripheral Nerve Field Stimulation for Persistent Post‐Herniorrhaphy Pain

Objectives:  Chronic post‐hernia pain is a common complication after inguinal herniorrhaphies. Peripheral nerve field stimulation (PNFS) and spinal cord stimulation (SCS) are two new promising treatment modalities. Four patients with persistent neuropathic post‐hernia pain were recruited for this prospective study.

Adult stem cells in neural repair: Current options, limitations and perspectives

Stem cells represent a promising step for the future of regenerative medicine. As they are able to differentiate into any cell type, tissue or organ, these cells are great candidates for treatments against the worst diseases that defy doctors and researchers around the world. Stem cells can be divided into three main groups: (1) embryonic stem cells; (2) fetal stem cells; and (3) adult stem cells. In terms of their capacity for proliferation, stem cells are also classified as totipotent, pluripotent or multipotent. Adult stem cells, also known as somatic cells, are found in various regions of the adult organism, such as bone marrow, skin, eyes, viscera and brain. They can differentiate into unipotent cells of the residing tissue, generally for the purpose of repair. These cells represent an excellent choice in regenerative medicine, every patient can be a donor of adult stem cells to provide a more customized and efficient therapy against various diseases, in other words, they allow the opportunity of autologous transplantation. But in order to start clinical trials and achieve great results, we need to understand how these cells interact with the host tissue, how they can manipulate or be manipulated by the microenvironment where they will be transplanted and for how long they can maintain their multipotent state to provide a full regeneration.

Equivalent Neurogenic Potential of Wild-Type and GFP-Labeled Fetal-Derived Neural Progenitor Cells Before and After Transplantation Into the Rodent Hippocampus

Introduction. The hippocampal formation is a specific structure in the brain where neurogenesis occurs throughout adulthood and in which the neuronal cell loss causes various demential states. The main goal of this study was to verify whether fetal neural progenitor cells (NPCs) from transgenic rats expressing green fluorescent protein (GFP) retain the ability to differentiate into neuronal cells and to integrate into the hippocampal circuitry after transplantation. Methods. NPCs were isolated from E14 (gestational age: 14 days postconception) transgenic-Lewis and wild-type Sprague-Dawley rat embryos. Wild-type and transgenic cells were expanded and induced to differentiate into a neuronal lineage in vitro. Immunocytochemical and electrophysiological analysis were performed in both groups. GFP-expressing cells were implanted into the hippocampus and recorded electrophysiologically 3 months thereafter. Immunohistochemical analysis confirmed neuronal differentiation, and the yield of neuronal cells was determined stereologically. Results. NPCs derived from wild-type and transgenic animals are similar regarding their ability to generate neuronal cells in vitro. Neuronal maturity was confirmed by immunocytochemistry and electrophysiology, with demonstration of voltage-gated ionic currents, firing activity, and spontaneous synaptic currents. GFP-NPCs were also able to differentiate into mature neurons after implantation into the hippocampus, where they formed functional synaptic contacts. Conclusions. GFP-transgenic cells represent an important tool in transplantation studies. Herein, we demonstrate their ability to generate functional neurons both in vitro and in vivo conditions. Neurons derived from fetal NPCs were able to integrate into the normal hippocampal circuitry. The high yield of mature neurons generated render these cells important candidates for restorative approaches based on cell therapy.