Inhibition of Invasion by Polyphenols from Citrus Fruit and Berries in Human Malignant Glioma Cells In Vitro.

BACKGROUND/AIM: The outlook for patients with high grade glioma (HGG) remains dismal. Hence, attention has focused on numerous innovative treatments. Our group has proposed a strategy on the use of a combination of polyphenols, as anti-invasive agents for the management of these neoplasms. MATERIALS AND METHODS: The aim of this study was to evaluate the in vitro effects of citrus flavonoids (tangeretin, nobiletin, naringin and limonin) and berry extracts (chokeberry, elderberry and bilberry) on selected mediators of invasion in 2 HGG cell cultures. RESULTS: The IC50 values could only be determined for tangeretin and chokeberry extract. The rest were non-functional in this context. Immunocytochemistry and flow cytometry results showed that chokeberry extract was most effective in down-regulating the expression of CD44. Similarly, RT-PCR data supported its ability to reduce gene expression of MMP-14 and EGFR. 2D invasion assays confirmed that inhibition is greater with chokeberry extract. CONCLUSION: Both polyphenols have anti-invasive potential but chokeberry extract is a stronger agent for glioma management.

The Role of Thalamus Versus Cortex in Epilepsy: Evidence from Human Ictal Centromedian Recordings in Patients Assessed for Deep Brain Stimulation.

BACKGROUND: The onset of generalized seizures is a long debated subject in epilepsy. The relative roles of cortex and thalamus in initiating and maintaining the different seizure types are unclear. OBJECTIVE: The purpose of the study is to estimate whether the cortex or the centromedian thalamic nucleus is leading in initiating and maintaining seizures in humans. METHODS: We report human ictal recordings with simultaneous thalamic and cortical electrodes from three patients without anesthesia being assessed for deep brain stimulation (DBS). Patients 1 and 2 had idiopathic generalized epilepsy whereas patient 3 had frontal lobe epilepsy. Visual inspection was combined with nonlinear correlation analysis. RESULTS: In patient 1, seizure onset was bilateral cortical and the belated onset of leading thalamic discharges was associated with an increase in rhythmicity of discharges, both in thalamus and cortex. In patient 2, we observed bilateral independent interictal discharges restricted to the thalamus. However, ictal onset was diffuse, with discharges larger in the cortex even though they were led by the thalamus. In patient 3, seizure onset was largely restricted to frontal structures, with belated lagging thalamic involvement. CONCLUSION: In human generalized seizures, the thalamus may become involved early or late in the seizure but, once it becomes involved, it leads the cortex. In contrast, in human frontal seizures the thalamus gets involved late in the seizure and, once it becomes involved, it lags behind the cortex. In addition, the centromedian nucleus of the thalamus is capable of autonomous epileptogenesis as suggested by the presence of independent focal unilateral epileptiform discharges restricted to thalamic structures. The thalamus may also be responsible for maintaining the rhythmicity of ictal discharges.

Intracranial stimulation for children with epilepsy.

OBJECTIVES: To evaluate the efficacy of intracranial stimulation to treat refractory epilepsy in children. METHODS: This is a retrospective analysis of a pilot study on all 8 children who had intracranial electrical stimulation for the investigation and treatment of refractory epilepsy at King's College Hospital between 2014 and 2015. Five children (one with temporal lobe epilepsy and four with frontal lobe epilepsy) had subacute cortical stimulation (SCS) for a period of 20-161 h during intracranial video-telemetry. Efficacy of stimulation was evaluated by counting interictal discharges and seizures. Two children had thalamic deep brain stimulation (DBS) of the centromedian nucleus (one with idiopathic generalized epilepsy, one with presumed symptomatic generalized epilepsy), and one child on the anterior nucleus (right fronto-temporal epilepsy). The incidence of interictal discharges was evaluated visually and quantified automatically. RESULTS: Among the three children with DBS, two had >60% improvement in seizure frequency and severity and one had no improvement. Among the five children with SCS, four showed improvement in seizure frequency (>50%) and one chid did not show improvement. Procedures were well tolerated by children. CONCLUSION: Cortical and thalamic stimulation appear to be effective and well tolerated in children with refractory epilepsy. SCS can be used to identify the focus and predict the effects of resective surgery or chronic cortical stimulation. Further larger studies are necessary.

Epilepsia partialis continua responsive to neocortical electrical stimulation.

Epilepsia partialis continua (EPC), defined as a syndrome of continuous focal jerking, is a rare form of focal status epilepticus that usually affects a distal limb, and when prolonged, can produce long-lasting deficits in limb function. Substantial electrophysiologic evidence links the origin of EPC to the motor cortex; thus surgical resection carries the risk of significant handicap. We present two patients with focal, drug-resistant EPC, who were admitted for intracranial video-electroencephalography monitoring to elucidate the location of the epileptogenic focus and identification of eloquent motor cortex with functional mapping. In both cases, the focus resided at or near eloquent motor cortex and therefore precluded resective surgery. Chronic cortical stimulation delivered through subdural strips at the seizure focus (continuous stimulation at 60-130 Hz, 2-3 mA) resulted in >90% reduction in seizures and abolition of the EPC after a follow-up of 22 months in both patients. Following permanent implantation of cortical stimulators, no adverse effects were noted. EPC restarted when intensity was reduced or batteries depleted. Battery replacement restored previous improvement. This two-case report opens up avenues for the treatment of this debilitating condition.

Perceptions of symptoms and expectations of advanced therapy for Parkinson's disease: preliminary report of a Patient-Reported Outcome tool for Advanced Parkinson's disease (PRO-APD).

BACKGROUND: What do patients expect from a treatment? A patient-centred approach to treatment is becoming necessary given the choices for invasive treatments for Parkinson's disease. Patient's perceptions of severity and expectations from complex therapies have not been studied. We describe the rationale and concept of developing a Patient-Reported Outcome (PRO) tool to assess perceptions of symptom severity and expectations of therapy. We report preliminary findings from use of the tool, association with clinical factors, and illustrate the potential use in individual patients awaiting therapy. METHODS: Patient symptoms were grouped into four domains, with 8 motor, 7 non-motor, 7 psychological and 4 social questions. For each question, symptom severity was rated on a Likert scale scoring from 0 (no problem) to 7 (perceived as a severe problem). Similarly, the expectation for each symptom to change after therapy was rated on a Likert scale: score -3 (expected to be very much worse) to + 3 (expected to be very much improved). RESULTS: 22 consecutive patients, routinely planned to receive one of Deep Brain Stimulation/Intrajejunal Levodopa Infusion/Apomorphine Infusion therapies, were recruited: 13 male, mean (+/-sd) age: 65.6 (+/-9.5) years, mean (+/-sd) disease duration: 14.3 (+/-5.7) years. Subjective severity scores are reported as mean (+/-sd) / maximum possible score: (i) motor 23.5 (+/-7.5) / 56, (ii) non-motor 15.5 (+/-5.6) / 49, (iii) cognitive - psychological 12.4 (+/-5.8) / 49, (iv) social 9.3 (+/-4.1) / 28. Expectation of change (improvement) scores are reported as mean (+/-sd) / maximum possible score of: (i) motor 14.0 (+/-5.6) / 24, (ii) non-motor 8.5 (+/-4.1) / 21, (iii) cognitive - psychological 7.4 (+/-4.4)/ 21, and (iv) social 5.5 (+/-2.8) / 12. For each domain, Spearman correlation coefficient showed significant associations between severity and expectation within-domain. CONCLUSION: This tool (PRO-APD) provides a description of perceived problem severity and expectation of treatments encompassing a holistic patient-driven view of care. PD patients about to receive complex therapy have moderately high perception of symptom load in multiple domains, and expect substantial improvements in multiple domains. These preliminary findings may be useful in documenting multi-domain symptoms, as well as counseling patients to help them reach realistic expectations and reduce potential dissatisfaction following therapy.

Cingulate epileptogenesis in hypothalamic hamartoma.

Hypothalamic hamartoma (HH) is a relatively rare cause of epilepsy, mainly affecting children. Nearly all patients develop gelastic seizures, often followed by other focal seizure types. Our case illustrates the mechanisms of epileptogenesis in HH. The patient developed gelastic attacks as a baby, and secondarily generalized seizures and drop attacks at 9 years of age. Magnetic resonance imaging (MRI) confirmed the presence of a HH. Presurgical assessment with intracranial electroencephalography (EEG) monitoring recorded gelastic seizures with generalized epileptiform activity. Functional stimulation of the hamartoma provoked gelastic attacks. Single pulse electrical stimulation (SPES) was used to identify epileptogenic cortex. SPES of the left cingular cortex provoked generalized responses similar to the spontaneous generalized discharges. Our results suggest that long-standing history of epilepsy in patients with HH may be related to additional sources of epileptogenic activity. Electrical stimulation performed in this patient provided additional data to favor the hypothesis of secondarily epileptogenesis in the cingulate gyrus independently from the primary origin in the HH.

Registered computed tomography images as an alternative to postimplantation magnetic resonance imaging in the assessment of subthalamic electrode placement.

Magnetic resonance imaging (MRI) after implantation of electrodes in the subthalamic nuclei is currently performed at a number of sites, but a recent adverse incident and changes in MRI technology may heighten safety concerns. In this report, it is demonstrated that given whole-head image data, registration of postimplantation computed tomography to preimplantation MRI can enable verification of the position of electrodes to an accuracy of 2 mm. This registration technique can remove the need for potentially risky postoperative MRI.

The clinical spectrum of epilepsy in children and adults with hypothalamic hamartoma.

PURPOSE: Hamartomas of the hypothalamus (HH) cause an uncommon and unusual epilepsy syndrome. The condition is recognized to affect children, but the presentation in adults is not well understood. We present 19 children and adult patients with HH, including three patients whose epilepsy began in adult life. The patterns of clinical presentation, evolution of the epilepsy from childhood to adult life, and electroclinical diagnostic features are presented. METHODS: Nineteen patients, both children and adults with HH and epilepsy, were evaluated clinically, with EEG, video-EEG, and magnetic resonance imaging (MRI) scanning. Seven patients underwent surgical resection of the hamartoma. Stereotactic thermocoagulation of the hamartoma was performed in two patients. RESULTS: Gelastic seizures occurred at onset of epilepsy in 15 of 16 early-onset cases. Subsequently, multiple seizures types occurred, which then evolved to mainly partial epilepsy with tonic or complex partial seizures (five of eight adults), or became entrenched symptomatic generalized epilepsy with atypical absences, drop attacks, and secondarily generalized seizures, and cognitive impairment (three of eight adults). In the adult-onset patients, gelastic seizures were not prominent, the epilepsy was milder, and they functioned normally. Stereotactic thermocoagulation of the hamartoma resulted in improvement in seizure control in two patients. CONCLUSIONS: Gelastic seizures are not a prominent feature of epilepsy in adult patients with HH. The epilepsy associated with HH, although severe at onset, can evolve into a milder syndrome in later life. For less severely affected patients, minimally invasive alternatives to the traditionally difficult open surgical treatment should be considered.