Central Nervous Disorders Research Articles

Regional anaesthesia and side effects: is it safe?

The availability of new local anaesthetics and the improvement of regional techniques has caused a great increase of central and peripheral blockades for anaesthesia as well as for postoperative pain. The increase of these blockades tends to increase the rate of complications. In a Pubmed research we found more than 400 articles about this topic. In the analysis of the literature we divided two major chapters: severe complications after central blockades and after peripheral nerve blocks. Analysis of the literature showed a lower incidence of serious complications associated with neuroaxial anaesthesia. It is important to underline that authors stressed the importance of predisposing factors like pre-existing peripheral or central neurological disease, arteriosclerotic disease, osteoporosis and spinal stenosis, diabetes, cancer, chronic alcohol abuse and steroid therapy. Otherwise, the most concern about peripheral nerve blocks is nerve injury and/or neuropathy due to potential toxicity of local anaesthetics or due a nerve lesion for needle trauma or infection. Even if the incidence of severe side effects is rare, it is very important that we approach this technique knowing well the risks (even if low) so that we can prevent them improving the outcome of patients. Nevertheless, there is again the need to have a large prospective study to investigate the real incidence of severe complications of central and peripheral blocks.

Evaluation of two interspecific recombinant viruses generated from two neurotropic bovine alphaherpesviruses: genomic characterization and virulence properties in the natural host

Bovine herpesvirus 1 (BoHV-1) and bovine herpesvirus 5(BoHV-5) are two closely related alphaherpesviruses thatinfect cattle. Both viruses are neurotropic but only BoHV-5 significantly replicates in the central nervous system andinduces neurological disease. We previously isolated 2interspecific recombinant viruses (R1 and R2) betweenBoHV-1 and BoHV-5 [1]. We report here on the precisecharacterization of the genetic backgrounds and on thevirulence assessment of these two BoHV-1/5 recom-binants in their natural host.An exhaustive PCR/sequencing approach led us to iden-tify the precise location of the two cross-over (CO) pointswhere recombination events occurred between the paren-tal strains. The first CO occurred in a 44 base pairs (bp)sequence of homology at the 3' end of the UL28 encodinggenes of BoHV-1 and BoHV-5. The resulting recombinant(R1) inherited 37% of the BoHV-1 genome. The rest of itsgenome (63%) is homologous to BoHV-5 containing thefinal region of the unique long (UL) region (from UL27 toUL0.5), the internal and terminal repeats (IR and TR) andthe unique short region (US). The second CO occurred ina 39 bp sequence of homology within the UL43 gene. Theresulting recombinant (R2) is mainly composed of BoHV-1 sequences (86%). It is homologous to BoHV-1 in a largeportion of the UL region (from UL43 to UL0.5), in the IR/TR and in the US region. BoHV-5 sequences account for14% of its genome content.In order to study the

Neonatal Neural Progenitor Cells and Their Neuronal and Glial Cell Derivatives Are Fully Permissive for Human Cytomegalovirus Infection

Congenital human cytomegalovirus (HCMV) infection causes central nervous system structural abnormalities and functional disorders, affecting both astroglia and neurons with a pathogenesis that is only marginally understood. To better understand HCMV's interactions with such clinically important cell types, we utilized neural progenitor cells (NPCs) derived from neonatal autopsy tissue, which can be differentiated down either glial or neuronal pathways. Studies were performed using two viral isolates, Towne (laboratory adapted) and TR (a clinical strain), at a multiplicity of infection of 3. NPCs were fully permissive for both strains, expressing the full range of viral antigens (Ags) and producing relatively large numbers of infectious virions. NPCs infected with TR showed delayed development of cytopathic effects (CPE) and replication centers and shed less virus. This pattern of delay for TR infections held true for all cell types tested. Differentiation of NPCs was carried out for 21 days to obtain either astroglia (>95% GFAP(+)) or a 1:5 mixed neuron/astroglia population (beta-tubulin III(+)/GFAP(+)). We found that both of these differentiated populations were fully permissive for HCMV infection and produced substantial numbers of infectious virions. Utilizing a difference in plating efficiencies, we were able to enrich the neuron population to approximately 80% beta-tubulin III(+) cells. These beta-tubulin III(+)-enriched populations remained fully permissive for infection but were very slow to develop CPE. These infected enriched neurons survived longer than either NPCs or astroglia, and a small proportion were alive until at least 14 days postinfection. These surviving cells were all beta-tubulin III(+) and showed viral Ag expression. Surprisingly, some cells still exhibited extended processes, similar to mock-infected neurons. Our findings strongly suggest neurons as reservoirs for HCMV within the developing brain.

Evoked Response Audiometry according to gender and age: findings and usefulness

SummaryAuditory evoked brainstem responses (ABR) is a non-invasive electrical potential registration which evaluates the auditory tract from the middle ear to the auditory cortex in the first 12 milliseconds (ms). The ABR is an important otoneurological evaluation.Aimconfirm the test's usefulness, major incidence and topography according to are range gender considering the absolute latencies of the waves and interpeak intervals.Materials and Methodwe retrospectively analyzed 403 tests from a private clinic in the city of Jundiaí-São Paulo State-Brazil, from patients suspected of auditory damage or central nervous disorder, and the patients were broken down according to gender and age.Results and ConclusionsABR is an important test to determinate the soundness of the auditory tract, the electrophysiological thresholds and topodiagnosis. We found no differences between type of loss and gender; there was a major incidence of retrocochlear findings among male patients between 12-20 years old; children under one year with risk factors did not present higher incidences of auditory findings when compared with all the population analyzed. The absolute latencies of waves I, III and V were higher in males, but the interpeak intervals were similar in both genders, showing that interval I-III was more frequently altered.

Dialysis Disequilibrium Syndrome and other treatment complications of extreme uremia: A rare occurrence yet not vanished

Severe uremia is now a rare occurrence in most developed nations, and yet is still present in many countries of the world. It includes clinical manifestations such as calciphylaxis and uremic frost, which are now rarely seen. Patients with extremely high levels of blood urea nitrogen (above 175 mg/dL) are at a higher risk of experiencing first-time hemodialysis-related complications, in particular dialysis disequilibrium syndrome (DDS). DDS is a central nervous disorder characterized by a wide variety of neurological symptoms that range from nausea and vomiting to even death due to cerebral edema. There are 2 main theories to explain its pathophysiology: the reverse urea effect, which considers that the shift of urea between brain intracellular space and plasma is not immediate, causing a higher concentration of urea within the brain and leading to cerebral edema. The second theory considers that after hemodialysis, patients have transient paradoxical metabolic acidosis within the central nervous system, displacing Na(+) and K(+) from organic anions, making them osmotically active and again leading to cerebral edema. The main goal is to prevent the occurrence of DDS, for which there are several proposed measures including continuous renal replacement therapies. Once established, treatment should be focused on supportive therapy. Another uncommon phenomenon described in patients who initiate hemodialysis is transient pulmonary leukocyte margination, which in conjunction with an inflammatory milieu, may lead to non-cardiogenic pulmonary edema. We present the case of a young adult with severe uremia who, despite application of recommended measures, developed DDS and non-cardiogenic pulmonary edema.

Neurological complications of medical anti-cancer therapies

This review describes the features of central and peripheral neurological disorders caused by anti-cancer chemotherapy and supportive medications, such as antiepileptic drugs, glucocorticosteroids and opioids, frequently used in cancer patients. Diffuse encephalopathy with or without epileptic seizures, cerebellar disorders and aseptic meningitis may occur after systemic administration of conventional drug doses, but their incidence is much higher when either high-dose chemotherapy, or intrathecal or intracarotid administration is used. Spinal cord and/or spinal root lesions have been reported after intrathecal administration of methotrexate or cytosinearabinoside. Anti-cancer chemotherapy is the leading cause of peripheral neuropathy in cancer patients. The main culprits are vinca alkaloids, platinum derivatives and taxanes. Anti-cancer chemotherapy has no significant toxic effect on muscle tissue, but heavy administration of glucocorticosteroids is a common cause of disabling, predominantly pelvic, muscle atrophy.

TSP-1 Secreted by Bone Marrow Stromal Cells Contributes to Retinal Ganglion Cell Neurite Outgrowth and Survival

BackgroundBone marrow stromal cells (BMSCs) are pluripotent and thereby a potential candidate for cell replacement therapy for central nervous system degenerative disorders and traumatic injury. However, the mechanism of their differentiation and effect on neural tissues has not been fully elucidated. This study evaluates the effect of BMSCs on neural cell growth and survival in a retinal ganglion cell (RGCs) model by assessing the effect of changes in the expression of a BMSC-secreted protein, thrombospondin-1 (TSP-1), as a putative mechanistic agent acting on RGCs.Methods and FindingsThe effect of co-culturing BMSCs and RGCs in vitro was evaluated by measuring the following parameters: neurite outgrowth, RGC survival, BMSC neural-like differentiation, and the effect of TSP-1 on both cell lines under basal secretion conditions and when TSP-1 expression was inhibited. Our data show that BMSCs improved RGC survival and neurite outgrowth. Synaptophysin, MAP-2, and TGF-β expression are up-regulated in RGCs co-cultured with BMSCs. Interestingly, the BMSCs progressively displayed neural-like morphology over the seven-day study period. Restriction display polymerase chain reaction (RD-PCR) was performed to screen for differentially expressed genes in BMSCs cultured alone or co-cultured with RGCs. TSP-1, a multifactorial extracellular matrix protein, is critically important in the formation of neural connections during development, so its function in our co-culture model was investigated by small interfering RNA (siRNA) transfection. When TSP-1 expression was decreased with siRNA silencing, BMSCs had no impact on RGC survival, but reduced neurite outgrowth and decreased expression of synaptophysin, MAP-2 and TGF-β in RGCs. Furthermore, the number of BMSCs with neural-like characteristics was significantly decreased by more than two-fold using siRNA silencing.ConclusionsOur data suggest that the TSP-1 signaling pathway might have an important role in neural-like differentiation in BMSCs and neurite outgrowth in RGCs. This study provides new insights into the potential reparative mechanisms of neural cell repair.

Status Epilepticus in the Pediatric Emergency Department

Status epilepticus (SE) is a common childhood condition often seen by emergency physicians. It occurs at a frequency of between 17 and 23 per 100 000, higher in younger children. Risk factors for SE include an acute symptomatic etiology, and for those children with underlying epilepsy, a remote symptomatic etiology and a younger age of epilepsy onset. Treatment paradigms vary by institution but should be rapid and aggressive. Underdosing of anticonvulsants and excessive lag between doses should be avoided. Identification of nonconvulsive and subclinical SE is often missed and requires a high index of suspicion. Refractory SE often requires an intensive care unit admission and the involvement of a neurologist. Etiologic evaluation should include a broad differential and be focused initially on treatable causes, including central nervous system infections, electrolyte and metabolic disorders, and trauma.

A Collagen-Binding Mimetic of Neural Cell Adhesion Molecule

A chimeric protein consisting of a cell-adhesive peptide derived from a neural cell adhesion molecule and a collagen-binding domain was synthesized using recombinant DNA technology. Here, we demonstrate that the chimeric protein binds to type I collagen and promotes the adhesion and neurite extension of hippocampus neurons. These results suggest that the chimeric protein has potential to provide microenvironments for neurons to adhere and survive in collagen-based matrices for use in cell-based therapies for central nervous disorders.

Aquaporin-4 Autoantibodies in a Paraneoplastic Context

The neuromyelitis optica IgG autoantibody (NMO-IgG) is a validated biomarker for NMO and an emerging spectrum of inflammatory central nervous system-demyelinating disorders. Its antigen is the astrocytic water channel aquaporin-4; NMO-IgG has not been described in a cancer context. To report (1) neurologic and oncologic correlates for patients incidentally identified as NMO-IgG seropositive in a blinded evaluation for paraneoplastic autoantibodies and (2) the frequency of cancer in NMO-IgG-seropositive patients. Observational, retrospective case series. Neuroimmunology Laboratory and Neurology Clinical Practice, Mayo Clinic College of Medicine. From 1998 to 2007, we detected NMO-IgG in 2 patient groups: (1) 31 patients (88% female) identified incidentally among 180 000 patients evaluated for paraneoplastic autoantibodies and (2) 141 patients identified through physician-requested serological evaluation for a suspected NMO-spectrum disorder. In the first group, clinical information was available for 28 patients (90%). An NMO-spectrum disorder was diagnosed in 26 patients (93%), of whom 6 had a neoplasm (5 carcinomas [2 breast, 1 lung, 1 thymic, and 1 uterine cervical] and 1 B-cell lymphoma) and 1 had monoclonal gammopathy. In 4 patients, NMO-related symptoms followed neoplasia detection (median, 14 [range 3-18] months), and in 2 patients, symptoms preceded neoplasia detection (by 5 and 3 months). Two patients had carcinoma (1 breast and 1 lung) without neurological evidence of an NMO-spectrum disorder. In the second group, neoplasms were recorded in 7 seropositive patients (5.0%) with a clinically diagnosed NMO-spectrum disorder: 3 carcinomas (all breast), 1 thyroid Hürthle cell, 1 carcinoid, 1 pituitary somatotropinoma, and 1 B-cell lymphoma. An eighth patient had monoclonal gammopathy. Aquaporin-4-specific IgG in some cases of NMO may reflect a paraneoplastic immune response. The clinical utility of this autoantibody as a cancer marker warrants prospective investigation.

Status Epilepticus

Status epilepticus (SE) in adults is a state of continuous seizures lasting more than 5 minutes, or rapidly recurrent seizures without regaining consciousness. The overall US and European estimated crude incidence rate of SE ranges from 6.8 to 41/100,000/yr. The etiologies of SE include primary central nervous system pathologies and systemic disorders. The two basic mechanisms involved in the genesis of SE are an excess of excitatory activity and a loss of normal inhibitory neurotransmission. Mortality associated with SE can be as high as 26% for the average adult. Early recognition and treatment are important for improving the chances for a good outcome. The first line of treatment is an intravenous benzodiazepine, with lorazepam being the current preferred agent. All patients with SE who remain with altered awareness 20 to 30 minutes after cessation of clinical seizures should undergo electroencephalographic studies, because up to 20% of patients without clinical evidence of seizures after initial treatment can have nonconvulsive SE.

Coraco- or costoclavicular paraosteoarthropathies in patients with severe central neurological disorders

Paraosteoarthropathy (POA) is a frequent disabling orthopedic complication after severe central neurological impairment. The hip is the most frequently affected joint (32.1%) followed by the elbow and the shoulder (25%). To evaluate coraco- and costoclavicular paraosteoarthropathy in patients with severe central neurological disorders. We report a series of five consecutive patients with severe central neurological disorders who developed a POA of the clavicular region (coracoclavicular or costoclavicular POA). Every patient underwent a clinical, radiological, and computed tomographic (CT) examination of the shoulder region. Four patients had a history of traumatic brain injury (TBI), and one an acute disseminated encephalomyelitis (ADEM). They developed POA of the clavicular region, although not around the glenohumeral joint. The patients complained of shoulder pain and of moderate limitation of movements. Radiological and CT examinations showed the presence of a bony formation in the coracoclavicular space in four cases and extending from the clavicle to the first rib around the costoclavicular joint in one case. In patients with severe brain lesions suffering from shoulder pain and moderate limitation of joint movements, POAs of the clavicular region are rare but should be considered.

マハラノビス・田口法（ＭＴ法）を用いた重心動揺の診断

Stabilograms of healthy subjects and clinical cases with vertigo and equilibrium disturbances were analyzed for the purpose of discriminating normal from abnormal stabilograms of patients with labyrinthine and non-labyrinthine disturbances using the Machalanobis-Taguchi (MT) Method.Method: Stabilograms were recorded with the eyes of the subjects open and closed for 60 seconds. The area, length/time, length/area, X- and Y- deviation, power spectrum, position and velocity vectors, and standard deviation, skewness and kurtosis of the amplitude histogram were measured. The total number of items measured was 69. The Machlanobis distance (MD) was calculated using these items.Result: (1) On analysis using healthy subjects as the unit space and clinical cases as the signal data, 64% of the signal cases showed MD values exceeding the discrimination value and could be diagnosed as abnormal. The MD and abnormal ratio in the cases with brain diseases were larger than those in the cases with labyrinthine diseases. (2) On analysis using cases with labyrinthine diseases as the unit space and cases with non-labyrinthine diseases as the signal data, 68% of the signal cases could be discriminated as non-labyrinthine disorders. (3) On examination of the percent contribution of the items, the factorial effect graph showed that almost all of the 69 items contributed to differentiation of the abnormal from normal stabilograms.Conclusion: The results suggest that the MT method is useful for the discrimination of stabilograms of healthy subjects from those of cases with labyrinthine and central nervous disorders.

Voltage-gated sodium channel blockers, 2001-2006: An overview

Voltage-gated sodium channel blockers have long been used in the therapy of various central nervous system diseases, including epilepsy, chronic pain, psychiatric disorders, and spasticity. Several old agents are available with suboptimal features. Their properties may be improved by enhancing their state-dependent channel blocking action, and/or sodium channel subtype selectivity. This paper gives a short overview on the present state of research in this field, and the chemical structures of old sodium channel blockers, and those of recently published or patented compounds with sodium channel blocking action.

Abnormal EMG muscle activity during gait in patients without neurological disorders

Abnormal muscle activity in patients with a central neurological disorder is commonly attributed to the underlying condition. This study considered abnormal muscle activity in orthopaedic patients who had no neurological involvement. Thirty-nine patients with a variety of orthopaedic problems underwent gait analysis, which included measurement of passive range of motion at the legs, manual muscle strength testing (MMST), instrumented gait analysis, and surface electromyography (EMG). Abnormal timing and duration of EMG activity was found in 51/77 legs. Muscle weakness was the most important cause of the abnormal EMG activity ( p < 0.001). However, abnormal muscle activity did not correspond to the joint which was controlled by the weak muscles. The triceps surae muscle, represented by the medial gastrocnemius, was significantly more involved (68.6%). Co-activity of the knee extensors and hamstrings was found in 17% of the affected legs. Three out of the 51 legs showed a continuous activity of the rectus femoris muscle in swing. These findings illustrate mechanisms to compensate for muscle weakness in stance in neurologically intact subjects.

Nongenomic Actions of Retinoids: Role of Nur77 and RXR in the Regulation of Apoptosis and Inflammation

Recent advances have suggested that nongenomic action of retinoids and their receptors represents an important mechanism by which they exert therapeutic effects. Here we review rapid biological responses triggered by retinoids and related molecules by focusing on novel nongenomic mechanisms involving cytoplasmic action of nuclear receptors Nur77 and retinoid X receptor (RXR) in the regulation of apoptosis and inflammation. A class of apoptosis-inducing compounds related to atypical retinoid AHPN/CD437 has emerged as promising therapeutic agents. They rapidly induce mitochondrial targeting of Nur77 and RXR and conversion of Bcl-2 from a cellular protector to a killer. Thus, understanding the nongenomic action of Nur77 and RXR may provide a rational basis to guide the design and development of new therapeutic agents for cancer, and skin, cardiovascular, metabolic and central nervous disorders. Keywords: Retinoids, Nur77, RXR, nongenomic, apoptosis, inflammation, AHPN, CD437

Respostas auditivas evocadas de latência média em doenças neurológicas

A presença das respostas auditivas evocadas de latência média permite-nos a avaliação da integridade do sistema auditivo periférico e central, incluindo os núcleos e vias auditivas existentes até ao nível da região subcortical. Desta forma, elas têm sido usadas para o estudo das alterações ocorridas em diferentes doenças neurológicas. OBJETIVOS: Verificar os valores dos períodos de latências destas respostas e detectar a presença das deflexões. CASUÍSTICA E MÉTODO: Foram avaliados 20 pacientes portadores de doenças neurológicas existentes ao nível central, de diferentes etiologias, sendo analisadas as várias deflexões, positivas e negativas, geradas pelos potenciais auditivos evocados de latência média. Os sujeitos da pesquisa foram escolhidos por conveniência e os dados coletados foram avaliados levando-se em consideração a relação interindivíduos. FORMA DE ESTUDO: Foi adotado o estudo de Coorte, com avaliação contemporânea. RESULTADOS: Foram analisados estatisticamente e mostram alterações significativas da respostas evocadas de latência média em pacientes neurológicos. CONCLUSÃO: Nesses pacientes ou havia supressão das deflexões estudadas ou suas latências estavam aumentadas, quando comparadas com os padrões normais.

Epidermal nevus syndrome

Epidermal nevus syndrome is a group of congenital neurocutaneous disorders characterized by epidermal nevi in association with cerebral, ocular, skeletal, and sometimes cardiac and renal abnormalities. These nevi have been classified according to their predominant component. We described a child presenting with inflammatory linear verrucous epidermal nevus on the head, which is an uncommon location. He also encountered ocular and central nervous system structural disorders.

Middle-latency auditory responses in neurological diseases

SummaryThe presence of middle-latency evoked auditory potentials allows for integrity evaluation of both peripheral and the central auditory systems, and also, that of the nucleus and auditory pathways of sub-cortical region. They have also been used to study alterations of these structures in different neurological diseases.Aimsthe aim of this study is to verify the latency of the middle-latency evoked auditory potentials and detect the presence of any deflections in subjects with neurological diseases.Materials and MethodsIn a clinical and prospective trial, 20 patients having central neurological diseases of various etiologies were evaluated and, positive and negative deflections produced by the middle-latency evoked auditory potentials in these patients were analyzed.ResultsData was statistically analyzed and showed significant modifications in middle-latency evoked auditory potentials.ConclusionThe authors concluded that patients with neurological disorders have either wave suppression or enlarged latency periods in relation to normal subjects.

A clinical study of corticospinal and peripheral conductions to proximal lower limb muscles

Objective To investigate the clinical utility of the newly developed “quadriceps combined technique” (QCT), which provides a global evaluation of the central and peripheral conduction to the proximal muscles of lower limbs, in a variety of central and peripheral neurological disorders. Methods Using surface recordings from the vastus medialis of the quadriceps muscle, we analyzed amplitudes and latencies of M response, patellar T reflex and motor evoked potentials (MEPs) after transcranial magnetic stimulation. We studied 180 patients with disorders impairing proximal strength of one or both lower limbs and compared them with 100 controls reported previously. Results The best parameters to detect central motor disorders were the central motor conduction time, MEP/M amplitude, T/MEP amplitude and latency ratios, whereas peripheral motor conduction time (PMCT) was best to assess peripheral disorders. The best parameter to identify proximal peripheral disorder was PMCTprox, whereas for distal peripheral disorders M amplitude and T/MEP amplitude ratio were most discriminative. Conclusions We report a simple, rapidly performed and well-tolerated method that improves proximal lower limbs evaluation, helps distinguishing pathologic from physiological brisk reflexes and provides clues for etiologic diagnosis. Significance The QCT is a sensitive and specific tool to investigate central and peripheral neurological disorders.