Asociación entre los polimorfismos genéticos de nucleótido único en genes transportadores ABC con la epilepsia farmacorresistente en la población española / Association between single nucleotide genetic polymorphisms in ABC transporter genes with drug-resistant epilepsy in the Spanish population

Introducción: El 30% de los pacientes con epilepsia no responde al tratamiento farmacológico. La presencia de polimorfismos genéticos de nucleótido único (SNP) en el individuo puede influir en la variabilidad de respuesta al tratamiento farmacológico. La hipótesis de transportadores plantea que la presencia de SNP en los genes que codifican las proteínas ABC repercutiría en la biodisponibilidad de los fármacos anticrisis en el foco epileptógeno, lo que ocasionaría refractariedad. El objetivo del presente estudio fue evaluar la asociación de 13 polimorfismos en los genes ABCB1, ABCC2, ABCC5 y ABCG2 con la epilepsia farmacorresistente (EFR) en población española. Sujetos y métodos: Se realizó un estudio de casos y controles que incluyó a 327 pacientes con epilepsia: 227 farmacorresistentes y 100 farmacocontrolados según los criterios de la Liga Internacional contra la Epilepsia. En el ADN de leucocitos de sangre periférica extraído se estudiaron los polimorfismos en los genes transportadores ABC. Se utilizó la plataforma tecnológica iPlex® Gold y Mass ARRAY. Se compararon las frecuencias alélicas y genotípicas del grupo de casos y del de controles, el valor de p, la odds ratio y los intervalos de confianza al 95%. Resultados: La frecuencia alélica y genotípica del presente estudio fue similar a la comunicada en las bases de datos poblacionales. En los SNP estudiados no se encontraron diferencias significativas (p > 0,05) en todos los modelos de herencia analizados. Conclusiones: Nuestros resultados sugieren que no existe asociación entre los polimorfismos analizados en los genes ABC con la EFR en población española. Sin embargo, otros estudios adicionales confirmarán o descartarán estos resultados.(AU)

Introduction: Almost a third of all patients with epilepsy (30%) fail to respond to pharmacological treatment. The presence of single nucleotide polymorphisms (SNPs) in the individual may influence the variability of the response to drug treatment. The transporter hypothesis posits that the presence of SNPs in the genes encoding ABC proteins would affect the bioavailability of antiseizure drugs at the epileptogenic focus, giving rise to refractoriness. The aim of the present study was to evaluate the association of 13 polymorphisms in the ABCB1, ABCC2, ABCC5 and ABCG2 genes with drug-resistant epilepsy (DRE) in a Spanish population. Subjects and methods: A case-control study was conducted involving 327 patients with epilepsy: 227 resistant to drug therapy and 100 in whom their medication enabled them to control their symptoms, according to International League Against Epilepsy criteria. In the peripheral blood leukocyte DNA that was extracted, polymorphisms in the ABC transporter genes were studied. The iPlex® Gold and Mass ARRAY technology platform was used. The allele and genotypic frequencies of the case and control groups, p-value, odds ratio and 95% confidence intervals were compared. Results: The allele and genotypic frequency of the present study was similar to that reported in population-based databases. For the SNPs studied, no significant differences (p > 0.05) were found in any of the inheritance models analysed. Conclusions: Our results suggest that there is no association between the polymorphisms analysed in the ABC genes and DRE in the Spanish population. Nevertheless, further studies will confirm or refute these results.(AU)

[Association between single nucleotide genetic polymorphisms in ABC transporter genes with drug-resistant epilepsy in the Spanish population]. / Asociación entre los polimorfismos genéticos de nucleótido único en genes transportadores ABC con la epilepsia farmacorresistente en la población española.

INTRODUCTION: Almost a third of all patients with epilepsy (30%) fail to respond to pharmacological treatment. The presence of single nucleotide polymorphisms (SNPs) in the individual may influence the variability of the response to drug treatment. The transporter hypothesis posits that the presence of SNPs in the genes encoding ABC proteins would affect the bioavailability of antiseizure drugs at the epileptogenic focus, giving rise to refractoriness. The aim of the present study was to evaluate the association of 13 polymorphisms in the ABCB1, ABCC2, ABCC5 and ABCG2 genes with drug-resistant epilepsy (DRE) in a Spanish population. SUBJECTS AND METHODS: A case-control study was conducted involving 327 patients with epilepsy: 227 resistant to drug therapy and 100 in whom their medication enabled them to control their symptoms, according to International League Against Epilepsy criteria. In the peripheral blood leukocyte DNA that was extracted, polymorphisms in the ABC transporter genes were studied. The iPlex® Gold and Mass ARRAY technology platform was used. The allele and genotypic frequencies of the case and control groups, p-value, odds ratio and 95% confidence intervals were compared. RESULTS: The allele and genotypic frequency of the present study was similar to that reported in population-based databases. For the SNPs studied, no significant differences (p > 0.05) were found in any of the inheritance models analysed. CONCLUSIONS: Our results suggest that there is no association between the polymorphisms analysed in the ABC genes and DRE in the Spanish population. Nevertheless, further studies will confirm or refute these results.

TITLE: Asociación entre los polimorfismos genéticos de nucleótido único en genes transportadores ABC con la epilepsia farmacorresistente en la población española.Introducción. El 30% de los pacientes con epilepsia no responde al tratamiento farmacológico. La presencia de polimorfismos genéticos de nucleótido único (SNP) en el individuo puede influir en la variabilidad de respuesta al tratamiento farmacológico. La hipótesis de transportadores plantea que la presencia de SNP en los genes que codifican las proteínas ABC repercutiría en la biodisponibilidad de los fármacos anticrisis en el foco epileptógeno, lo que ocasionaría refractariedad. El objetivo del presente estudio fue evaluar la asociación de 13 polimorfismos en los genes ABCB1, ABCC2, ABCC5 y ABCG2 con la epilepsia farmacorresistente (EFR) en población española. Sujetos y métodos. Se realizó un estudio de casos y controles que incluyó a 327 pacientes con epilepsia: 227 farmacorresistentes y 100 farmacocontrolados según los criterios de la Liga Internacional contra la Epilepsia. En el ADN de leucocitos de sangre periférica extraído se estudiaron los polimorfismos en los genes transportadores ABC. Se utilizó la plataforma tecnológica iPlex® Gold y Mass ARRAY. Se compararon las frecuencias alélicas y genotípicas del grupo de casos y del de controles, el valor de p, la odds ratio y los intervalos de confianza al 95%. Resultados. La frecuencia alélica y genotípica del presente estudio fue similar a la comunicada en las bases de datos poblacionales. En los SNP estudiados no se encontraron diferencias significativas (p > 0,05) en todos los modelos de herencia analizados. Conclusiones. Nuestros resultados sugieren que no existe asociación entre los polimorfismos analizados en los genes ABC con la EFR en población española. Sin embargo, otros estudios adicionales confirmarán o descartarán estos resultados.

Neuronal and mixed neuronal glial tumors associated to epilepsy. A heterogeneous and related group of tumours.

The group of brain tumors with mature components encompasses several pathological entities including: the ganglioneuroma; the gangliocytoma; the ganglioglioma; the desmoplastic ganglioglioma; the neurocitoma and a group of glioneuronal hamartomatous tumorous lesions, such as meningoangiomatosis. The dysembryoplastic neuroepithelial tumor is characterized by the presence of multiple cortical nodules made up of small, oligo-like cells and a myxoid pattern rich in mucopolysaccharides. Mature neuronal cells are frequently detected throughout the tumor. Most of them are associated with microhamartias in the adjacent brain and pharmacoresistant epilepsy. The excellent prognosis of the majority of these tumors and the potential for malignant transformation of the glial component in the ganglioglioma are the two most remarkable findings. Histological signs of anaplasia and greater mitotic and proliferative activities are associated with local recurrences. Atypical neurocytomas occur only exceptionally. Treatment choices are surgical resectioning and, in those cases presenting greater proliferative activity and cytological atypia, postoperative radiotherapy may be recommended. This paper reviews this heterogeneous group of neoplasms and hamartomatous lesions, pointing out presumable transitions among the different types of mixed neuronal and glial brain tumors. A single term of "mixed neuronal-glial tumors" is defended, distinguishing different subgroups of tumors, depending on the predominant cellular component.

Intracranial pressure dynamics in clinical practice: online PC-based ICP monitoring system.

Correct patient management involves determining the exact point on the intracranial pressure/volume (P/V) curve that corresponds to the patient; this requires calculating intracranial elastance (IE). Intracranial pressure (ICP) monitoring systems should provide the necessary information for this purpose. An ICP monitoring unit is presented that acquires ICP, systemic arterial pressure (SAP) and airway pressure (AWP). The cerebral perfusion pressure (CPP) and the mean values and the peak-to-peak values of the two of them (ICPmean, SAPmean, ICPp-p, SAPp-p,) are calculated. Graphs display the temporal evolution (TE) of the ICP and SAP, as well as histograms of the ICP (%) and intracranial pulse amplitude (ICPAmP) with respect to the ICP or CPP during the preceding 3, 6, 12 or 24 h of monitoring. By digital filtering the ICP respiratory and cardiac components (RCICP, CCICP) are calculated. Finally, the pulse amplitudes (AmP) of the ICP, CCICP and RCICP are computed, as well as the average pulses per minute of SAP, CCICP, AWP and RCICP. Two off-line pulse-amplitude and pulse-morphology oriented toolkits display the afore-mentioned curves, histograms and average pulses per minute, and other additional ones, in order to achieve a deeper patient monitoring study.

Selective changes in the microorganization of the human epileptogenic neocortex revealed by parvalbumin immunoreactivity.

The microanatomy of the human lateral temporal cortex removed from patients with intractable temporal lobe epilepsy was studied using correlative light and electron microscopic immunocytochemical methods for the localization of the calcium-binding protein parvalbumin (PV). PV immunostaining was mainly used to label a subpopulation of powerful cortical inhibitory interneurons that have been shown to be lost at epileptic foci in certain animal models of epilepsy. In the human neocortex with normal appearance, we identified the same local neuronal circuitry as in the normal monkey cortex, but in some regions of the same cortex, a fine disorganization of neuronal circuits (loss of inhibitory neurons and presumptive thalamocortical terminals) was found. This abnormal circuitry may interfere with normal cerebral activity in epileptic patients. These results also indicate that PV immunoreactivity can be a useful tool to study normal and abnormal synaptic circuits in the human cerebral cortex.

Surgical treatment for epilepsy. Results after a minimum follow-up of five years.

Forty-two patients have been surgically treated for medically uncontrollable epilepsy, using the Talairach and Bancaud methodology. The mean age of the patients was 19 years (range 6-54 years). The location of the epileptogenic zone was:frontal in 18 patients, temporal in 14, temporo-parieto-occipital junction in 4, parietal in 4 and occipital in 2. The overall surgical results are: 20 patients are seizure free and 6 patients had occasional seizures (62% success rate). There has been a significant decrease in the number of seizures in 12 patients. The seizures persist in 4 patients. Only two patients, both with a parietal focus, presented additional postoperative neurological deficit (mild paresis in the contralateral lover limb). This was preoperatively foreseen, and accepted by the patient, on guarantees of the removal of the epileptogenic zone and amelioration of seizures.

Trans-fissural or trans-sulcal approach versus combined stereotactic-microsurgical approach.

The combined stereotactic-microsurgical approach has been used mainly to allow the removal of small subcortical lesions, determining their location and the route to be followed. In our experience, this approach has been most useful in 5 cases of small paraventricular AVMs and another 6 small deep-seated tumoural lesions. Since the availability of MRI, we have systematically applied Yasargil's proposal to perform dissection of the cisterns or sulci to reach a lesion with minimal or no injury to normal neuroanatomy. Assisted by Computer Aided Design software, we can superimpose the MR images with those provided by conventional or digital angiography (mainly the venous phase). MRI allows us to select a route or pathway through a sulcus, and angiography helps us in locating it on the brain surface. We have applied this technique systematically during the past year, and can report 20 cases (1 AVM, 12 tumoural lesions, 1 abscess and 6 haematomas). This trans-fissural or trans-sulcal approach has allowed us resection with minimal surgical damage, after a prompt and precise location. We think that both methods are not mutually exclusive, although the trans-sulcal approach is more adequate because of less discomfort for the patient, the smaller cerebral parenchyma injury and greater anatomofunctional information for the surgeon.

The immediate and long-term effects of mannitol and glycerol. A comparative experimental study.

A prolonged experimental situation of focal vasogenic oedema, producing mild intracranial hypertension, was developed. The aim was to study the immediate and long-term effects of repeated infusions of mannitol and glycerol on intracranial pressure (ICP) and cerebral blood flow (CBF). Eighteen goats were operated on twice to implant: an epidural latex balloon in each cerebral hemisphere to measure ICP; an electromagnetic flowmeter around both internal maxillary arteries (the only cerebral blood input), after tying the extracranial branches, to measure the CBF; and two femoral catheters to measure blood pressure (BP) and for intravenous infusion (IV). Three groups of 6 goats each were formed: A) control; the BP and bilateral ICPs and CBFs were recorded under basal conditions and every 4 hours for 3 days after a cold injury (CI) was provoked; B) 20% mannitol solution 1 g/kg body weight injected every 12 hr starting at 24 hr post-CI; and C) 10.1% glycerol solution 0.5 g/kg body weight, administered as mannitol. Glycerol, as compared to mannitol, presents the following major differences among its immediate post infusion effects: a lesser decrease in ICP, but no rebound phenomenon; lesser elevation of BP; CBF increases more gradually and constantly. Long-term effects with mannitol consisted of a rebound phenomenon observed in ICP during the last 12 hr. In all 3 groups, it was observed that CBF increases in relation to the ICP level.

Effects of high-frequency jet ventilation on intracranial pressure and cerebral elastance in dogs.

In order to assess the effect of high-frequency jet ventilation (HFJV) on intracranial pressure (ICP) and cerebral elastance (CE), a model of progressive intracranial hypertension was developed. Six healthy dogs were ventilated using HFJV and another six with conventional mechanical ventilation. ICP and its pulse amplitude (Amp) were measured by means of an epidural transducer, and CE was assessed by analysis of the relationship between the Amp and the mean ICP. The mean ICP, under basal conditions, did not differ between the two forms of ventilation, the Amp and the slope of the relationship Amp/ICP being lower with HFJV (p less than .001). Since the lower airway pressure created with HFJV was the only difference, it is suggested that the differences found in this study are related to these pressures.

Traumatic false aneurysms of the middle meningeal artery.

The authors report a rare case of traumatic false aneurysm of the middle meningeal artery associated with a delayed contralateral extradural hematoma. The extradural hematoma was evacuated, and the pseudoaneurysm was removed to avoid delayed rupture. The literature on traumatic aneurysms is reviewed.

Intracranial gangliogliomas.

Five cases of intracranial gangliomas in their clinical, diagnostic and surgical aspects are presented. In four cases we arrived at the diagnosis by CT-scan, which showed in all of them, calcified lesions without a mass effect. Total surgical resection was performed in four cases, and there is no evidence of recurrence either clinically or in the CT-scan after different follow-up periods. Although infrequent, these kinds of tumours should enter the differential diagnosis at any time when there a calcified mass exists in children or young patients with a long history of seizures. In our experience, seizures were the most important sign in all cases with supratentorial gangliogliomas.

Medically intractable epilepsies of tumoural aetiology. Report of 4 cases treated according to the method described by J. Talairach et al.

The authors present 4 patients with medically uncontrollable epilepsy of tumoural aetiology (grade I-II gliomas). In two of them, CT scan showed probable neoplastic lesions, located deeply in the left frontal and right temporal lobes respectively, reflected in the SEG studies only in the second case. The other two were patients with left frontal gliomas in whom seizures did not disappear after removal of the tumour. After SEEG studies defined the epileptogenic zone and the lesion and these were removed, complete suppression of the seizures was achieved in two patients and the other two only unfrequently suffered seizures. We emphasize the importance of SEEG studies for success in treating patients with gliomata previously diagnosed by CT scan, and who have seizures uncontrolled by anticonvulsants as the only symptom.