Marios S. Themistocleous

High incidence of MGMT and RARbeta promoter methylation in primary glioblastomas: association with histopathological characteristics, inflammatory mediators and clinical outcome.

Glioblastomas, the most frequent primary brain tumors in adults, are characterized by a highly aggressive, inflammatory and angiogenic phenotype. Methylation of CpG islands in cancer-related genes may serve as an epigenetic biomarker for glioblastoma diagnosis and prognosis. The aim of this study was to analyze the methylation status of four critical tumor-associated genes (MGMT, RARβ, RASSF1A, CDH13), and investigate possible links with inflammatory (interleukin (IL)-6, IL-8) and angiogenic mediators (vascular endothelial growth factor (VEGF), cyclooxygenase (COX)-2) and clinical outcome in 23 glioma samples (6 grade II astrocytomas, 17 grade IV glioblastomas). RARβ and MGMT genes were more frequently methylated in 70.58% and 58.8% of glioblastomas, respectively. RASSF1A and CDH13 displayed a similar methylation frequency (23.52%) in glioblastomas. No gene methylation was observed in grade II astrocytomas. Tumor grade correlated positively with MGMT and RARβ methylation (P = 0.005 and P = 0.019, respectively) and the extent of necrosis (P= 0.001 and P= 0.003). Interestingly, the marker of chronic inflammation, IL-6, was positively associated with methylation of MGMT (P = 0.004), RARβ (P = 0.002), and RASSF1A (P = 0.0081) as well as the total number of methylated genes (P < 0.0001), indicating the important role of IL-6 in maintaining promoter methylation of these genes. VEGF expression correlated positively with MGMT and RARβ methylation although these relationships were of marginal significance (P= 0.0679 and P = 0.0757). Kaplan-Meier univariate survival analysis indicated an unfavorable survival period in patients with MGMT methylation compared with those without methylation (P= 0.0474). Our study highlights the implication of MGMT and RARβ methylation in the aggressive phenotype of primary glioblastomas. The association of MGMT methylation with clinical outcome indicates its potential prognostic value.

Interobserver variability, and visual and quantitative parameters of 123 I-FP-CIT SPECT (DaTSCAN) studies

ObjectiveTo evaluate the degree of interobserver agreement in the visual interpretation of 123I-FP-CIT studies and to investigate for potential associations between visual and semi-quantitative parameters.MethodsEighty-nine 123I-FP-CIT studies were blindly reviewed by 3 independent observers: a consultant, a resident doctor and a radiographer. They classified every study as either “normal” or “abnormal” and assigned visual 123I-FP-CIT uptake scores (2: normal, 1: reduced and 0: no uptake) in basal ganglia nuclei (right and left putamina and caudate nuclei) on every scan. Striatal 123I-FP-CIT binding ratios were calculated using crescent-ROI software. The interobserver agreement for the interpretation of studies and for visual score assignment was evaluated by means of κ statistics. We investigated for associations of binding ratios with visual scores and clinical parameters; patients’ clinical diagnoses served as the reference standard.ResultsThere was excellent interobserver agreement (κ 0.89–0.93) in classifying studies as “normal” or “abnormal” and fine agreement in assignment of visual scores (κ 0.71–0.80 for putamina and 0.50–0.79 for caudate nuclei). Nuclei with scores of 1 and 0 showed significantly reduced binding ratios (about 30 and 50%, respectively) compared with the nuclei scored as 2. ROC analysis indicated the optimal cutoff point of striatal binding ratio at 3.8 (sensitivity 98.5%, specificity 95%) for the detection of parkinsonian syndromes. Striatal binding ratios were negatively associated with age in normal subjects and disease duration in Parkinson’s disease patients.ConclusionVisual interpretation of 123I-FP-CIT studies showed very good interobserver agreement. We found significant associations among visual, semi-quantitative and clinical parameters.

Treatment of idiopathic head drop (camptocephalia) by deep brain stimulation of the globus pallidus internus

Deep brain stimulation of the globus pallidus internus has been shown to be beneficial in a small number of patients suffering from axial dystonias. However, it has not yet been reported as an effective treatment for the alleviation of idiopathic head drop. The authors describe a 49-year-old woman with idiopathic cervical dystonia (camptocephalia) who was unable to raise her head > 30 degrees when standing or sitting; her symptoms would abate when lying down. This disabling neurological condition was treated successfully with bilateral chronic electrical stimulation of the globus pallidus internus.

Emerging Role of Linker Histone Variant H1x as a Biomarker with Prognostic Value in Astrocytic Gliomas. A Multivariate Analysis including Trimethylation of H3K9 and H4K20

Although epigenetic alterations play an essential role in gliomagenesis, the relevance of aberrant histone modifications and the respective enzymes has not been clarified. Experimental data implicates histone H3 lysine (K) methyltransferases SETDB1 and SUV39H1 into glioma pathobiology, whereas linker histone variant H1.0 and H4K20me3 reportedly affect prognosis. We investigated the expression of H3K9me3 and its methyltransferases along with H4K20me3 and H1x in 101 astrocytic tumors with regard to clinicopathological characteristics and survival. The effect of SUV39H1 inhibition by chaetocin on the proliferation, colony formation and migration of T98G cells was also examined. SETDB1 and cytoplasmic SUV39H1 levels increased from normal brain through low-grade to high-grade tumors, nuclear SUV39H1 correlating inversely with grade. H3K9me3 immunoreactivity was higher in normal brain showing no association with grade, whereas H1x and H4K20me3 expression was higher in grade 2 than in normal brain or high grades. These expression patterns of H1x, H4K20me3 and H3K9me3 were verified by Western immunoblotting. Chaetocin treatment significantly reduced proliferation, clonogenic potential and migratory ability of T98G cells. H1x was an independent favorable prognosticator in glioblastomas, this effect being validated in an independent set of 66 patients. Diminished nuclear SUV39H1 expression adversely affected survival in univariate analysis. In conclusion, H4K20me3 and H3K9 methyltransferases are differentially implicated in astroglial tumor progression. Deregulation of H1x emerges as a prognostic biomarker.

Malignant neuroleptic syndrome following deep brain stimulation surgery: a case report

BackgroundThe neuroleptic malignant syndrome is an uncommon but dangerous complication characterized by hyperthermia, autonomic dysfunction, altered mental state, hemodynamic dysregulation, elevated serum creatine kinase, and rigor. It is most often caused by an adverse reaction to anti-psychotic drugs or abrupt discontinuation of neuroleptic or anti-parkinsonian agents. To the best of our knowledge, it has never been reported following the common practice of discontinuation of anti-parkinsonian drugs during the pre-operative preparation for deep brain stimulation surgery for Parkinsons disease.Case presentationWe present the first case of neuroleptic malignant syndrome associated with discontinuation of anti-parkinsonian medication prior to deep brain stimulation surgery in a 54-year-old Caucasian man.ConclusionThe characteristic neuroleptic malignant syndrome symptoms can be attributed to other, more common causes associated with deep brain stimulation treatment for Parkinsons disease, thus requiring a high index of clinical suspicion to timely establish the correct diagnosis. As more centers become eligible to perform deep brain stimulation, neurologists and neurosurgeons alike should be aware of this potentially fatal complication. Timely activation of the deep brain stimulation system may be important in accelerating the patients recovery.

Restoration of erect posture by deep brain stimulation of the globus pallidus in disabling dystonic spinal hyperextension

Dystonia is a movement disorder notoriously difficult to treat. While primary dystonia is classically considered to respond well to deep brain stimulation (DBS), treatment of secondary dystonia yields variable results. Patient selection should be done on a case-by-case basis. Clearly, there is a need to accumulate additional information with regard to prognostic factors that may aid neurosurgeons in selecting those patients in whom the disorder is most likely to respond favorably to pallidal DBS. The authors report the case of a 29-year-old man with secondary dystonia due to perinatal hypoxia. The most prominent symptom was what we have termed ectatocormia—that is, severe, fixed truncal hyperextension and retrocollis, exacerbated by phasic, twisting movements of the trunk and head. This made it impossible for the patient to maintain a normal upright posture or to walk. The patient underwent bilateral DBS of the globus pallidus internus (GPi), and the authors observed impressive improvement in motor abilit...

Antiepileptics for Post-Traumatic Seizure Prophylaxis after Traumatic Brain Injury

Traumatic brain injury (TBI) is an important public health concern plagued by high rates of mortality and significant long-term disability in many survivors. Post-traumatic seizures (PTS) are not uncommon following TBI, both in the early (within 7 days post-injury) and late (after 7 days post-injury) period. Due to the potential of PTS to exacerbate secondary injury following TBI and the possibility of developing post-traumatic epilepsy (PTE), the medical community has explored preventative treatment strategies. Prophylactic antiepileptic drug (AED) administration has been proposed as a measure to reduce the incidence of PTS and the ultimate development of PTE in TBI patients. In this topical review, we discuss the pathophysiologic mechanisms of early and late PTS and the development of PTE following TBI, the pharmacodynamic and pharmacokinetic properties of AEDs commonly used to prevent post-traumatic seizures, and summarize the available clinical evidence for employing AEDs for seizure prophylaxis after TBI.

Antithrombotic Treatment Management in Patients with Intracerebral Hemorrhage: Reversal and Restart

BACKGROUND Intracerebral hemorrhage is the pathological accumulation of blood within the brain. It is a type of stroke more likely to be lethal or to severely disable the patient and results from a wide variety of causes. On the other hand antithrombotic therapy is used for the prevention or/and the therapy of thromboembolic episodes. Antithrombotic drugs are very effective in reducing risk or mortality rate after a thromboembolic event, yet they are associated with significant hemorrhages. OBJECTIVE The aim of this article is to review current literature for intracerebral hemorrhage and antithrombotic therapy and offer recommendations on the reversal, the discontinuation and the resumption of antithrombotic therapy. METHODS AND MATERIALS Current literature has been reviewed for intracerebral hemorrhage associated with three major categories of patients, those with atrial fibrillation, those with prosthetic mechanical valves and those with venous thromboembolism. Antithrombotic therapy is categorized in antiplatelet agents and anticoagulants. The risk of intracerebral hemorrhage, of a thromboembolic event and of a rebleeding with or without antithrombotic therapy was also reported. CONCLUSION Although no one can deny the usefulness of antithrombotic therapy a therapeutic strategy should be developed in order to optimize the clinical decision of stopping, reversing and restarting antithrombotic treatment. This review concludes in strong recommendations, yet a multidisciplinary panel by a stroke physician or neurologist, a cardiologist, a neuroradiologist and a neurosurgeon should evaluate the benefits and the risks for each patient and decide the best therapeutic strategy.

Post-traumatic tremor in child after mild head trauma

Despite the fact that movement disorders can be noted after severe traumatic brain injury (TBI), there are very few cases in the literature regarding children with a mild head injury. In addition, their pathophysiological mechanism, radiological features, and treatment options have not been well described yet. Hereby, we report a case of a 3-year-old girl who suffered a head injury after a two-meter fall, resulting in generalized body tremor and dystonia.

Intrathecal Baclofen Therapy for Painful Muscle Spasms in a Patient with Friedreich’s Ataxia

Friedreich’s ataxia (FA) is the most frequent hereditary ataxia syndrome, while painful muscle spasms and spasticity have been reported in 11–15% of FA patients. This report describes the successful management of painful spasms in a 65-year-old woman with FA via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments. To our knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague. Taking into consideration the suggested spinal atrophy in FA, the clinical resemblance of FA and chronic spinal injury muscle spasms, together with the rapid ITB therapy effectiveness in alleviating FA muscle spasms, we attempted to suggest a putative pathophysiological mechanism acting at the spinal level and possibly explained by the presence of independent spinal locomotor systems producing muscle spasms. Specifically, overexcitement of these centers, due to loss of normal regulation from upper CNS levels, may result in the uncontrolled firing of secondary motor neurons and may be the key to producing muscle spasms. However, further research under experimental and clinical settings seems to be necessary.