Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer.

PURPOSE: Prostate specific antigen has limited performance in detecting prostate cancer. The transcription factor GATA2 is expressed in aggressive prostate cancer. We analyzed the predictive value of urine extracellular vesicle GATA2 mRNA alone and in combination with a multigene panel to improve detection of prostate cancer and high risk disease. MATERIALS AND METHODS: GATA2 mRNA was analyzed in matched extracellular vesicles isolated from urines before and after prostatectomy (16) and paired urine and tissue prostatectomy samples (19). Extracellular vesicle GATA2 mRNA performance to distinguish prostate cancer and high grade disease was tested in training (52) and validation (165) cohorts. The predictive value of a multigene score including GATA2, PCA3 and TMPRSS2-ERG (GAPT-E) was tested in both cohorts. RESULTS: Confirming its prostate origin, urine extracellular vesicle GATA2 mRNA levels decreased significantly after prostatectomy and correlated with prostate cancer tissue GATA2 mRNA levels. In the training and validation cohort GATA2 discriminated prostate cancer (AUC 0.74 and 0.66) and high grade disease (AUC 0.78 and 0.65), respectively. Notably, the GAPT-E score improved discrimination of prostate cancer (AUC 0.84 and 0.72) and high grade cancer (AUC 0.85 and 0.71) in both cohorts when compared with each biomarker alone and PT-E (PCA3 and TMPRSS2-ERG). A GAPT-E score for high grade prostate cancer would avoid 92.1% of unnecessary prostate biopsies, compared to 61.9% when a PT-E score is used. CONCLUSIONS: Urine extracellular vesicle GATA2 mRNA analysis improves the detection of high risk prostate cancer and may reduce the number of unnecessary biopsies.

[Clinical outcome of distinct Aicardi syndrome phenotypes]. / Síndrome de Aicardi: variabilidad fenotípica y factores pronósticos.

OBJECTIVE: Three cases of Aicardi Syndrome were diagnosed in our hospital. This syndrome is a rare, female-restricted genetic disease, characterized by agenesis of the corpus callosum, other central nervous system malformations, and chorioretinal lacunae. We have compared these cases with other cases of Aicardi Syndrome described in the world literature. METHODS: We have reported the three cases of Aicardi Syndrome and detailed the important heterogeneity of phenotypic features and clinical severity. RESULTS: The most benign case (case number 1) was characterized by mild ocular morbidity, absence of both migration abnormalities and epilepsy, and normal psychomotor development. Case number 2 achieved long-term survival with mild ocular alterations, but had severe retardation in psychomotor development. Case number 3 had the most severe ocular abnormalities which evolved rapidly and resulted in early death. CONCLUSIONS: Aicardi Syndrome can be phenotypically heterogeneous, presenting with substantial variability in the severity of clinical features such as psychomotor development and survival. Our study indicates that cortical migration abnormalities and retinal lesions may be useful prognostic factors.

[The efficacy of lamotrigine in refractory infantile epilepsy]. / Eficacia de la lamotrigina en la epilepsia infantil rebelde.

INTRODUCTION: The new antiepileptic drugs should also be evaluated outside clinical trials. OBJECTIVE: To study the efficacy of treatment with lamotrigine in everyday neuropaediatric clinical practice. PATIENTS AND METHODS: We made a longitudinal study of all patients treated with lamotrigine in a hospital outpatients department. The efficacy was evaluated by: 1. The number of patients showing partial response (>/=50% reduction in seizures as compared to the basal rate), and total response maintained throughout the follow up period. 2. Duration of treatment, studied using the Kaplan Meier method. RESULTS: 80 patients treated with LTG had as the aetiology of their seizures: idiopathic 3.7%, cryptogenic (51.3%) and symptomatic (45%). We found there to be partial control during the first three months of treatment in 60.8% of the patients, which was maintained after 12 months in 43.1%, and after three years in 30.7%. Total control of the seizures after three months was found in 14.8%, after twelve months in 9.8% and after three years in 3.8%. The probability of treatment with lamotrigine being maintained for six months was 86%, for twelve months 61% and for three years 31%. Lamotrigine was suspended in 38 patients (47.5%). Side effects were reported in five cases. CONCLUSIONS: In clinical practice, the therapeutic effect not only consists of the percentage of patients who respond to treatment, but also the length of time this response is maintained. In our study, both measurements of effect showed results similar to those with classical antiepileptic drugs.

Multilocular hydrocephalus: ultrasound studies of origin and development.

Multilocular hydrocephalus is a complication of neonatal hydrocephalus. Its main feature is the presence of multiple cysts inside the ventricles, which requires a specific therapeutic approach. The case of a preterm infant with intracranial hemorrhage grade II-III and central nervous system infection is reported. The cysts developed at the subependymal layer in the posterior area of the patient's thalamus. Their growth and development were charted by ultrasound imaging for several weeks. These types of cysts may grow to occupy the totality of the lateral ventricles, isolating the temporal horns. Of all the reviewed pathogenic mechanisms, we support the hypothesis of an inflammatory vasculitis at the subependymal level, with the subsequent infarct giving rise to the cysts. The osmotic pressure within the cavities, rather than intraventricular fluid, would account for the enlargement of the cysts.

Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct.

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia and pathologically by neural degeneration of the caudate and putamen. Studies of metabolite excretion allowed us to categorize 43 GA I Spanish patients into two groups: group 1 (26 patients), those presenting with high excretion of both glutarate and 3-hydroxyglutarate, and group 2 (17 patients), those who might not be detected by routine urine organic acid analysis because glutarate might be normal and 3-hydroxyglutarate only slightly higher than controls. Single-strand conformation polymorphism (SSCP) screening and sequence analysis of the 11 exons and the corresponding intron boundaries of the GCDH gene allowed us to identify 13 novel and 10 previously described mutations. The most frequent mutations in group 1 were A293T and R402W with an allele frequency of 30% and 28%, respectively. These two mutations were also found in group 2, but always in heterozygosity, in particular in combination with mutations V400M or R227P. Interestingly, mutations V400M and R227P were only found in group 2, and at least one of these mutations was found in 11 of 15 unrelated alleles, accounting together for 53% of the mutant alleles in group 2. Therefore, it seems clear that two genetically and biochemically distinct groups of patients exist. The severity of the clinical phenotype seems to be closely linked to the development of encephalopathic crises rather than to residual enzyme activity or genotype. Comparison of GCDH protein with other acyl-CoA dehydrogenases (whose x-ray crystal structure has been determined) reveals that most of the mutations identified in GCDH protein seem to affect folding and tetramerization, as has been described for a number of mutations affecting mitochondrial beta-oxidation acyl-CoA dehydrogenases.

Genetic refinement of the hereditary neuralgic amyotrophy (HNA) locus at chromosome 17q25.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal neuropathy. HNA is characterised by episodes of painful brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. Single episodes are commonly preceded by non-specific infections, immunisations or parturition. Mild dysmorphic features and short stature are present in some HNA families, but absolute co-segregation with HNA has not been described. To refine the previously described HNA locus on chromosome 17q25, we performed a genetic linkage study in five HNA families with different geographic origins. Significant linkage was obtained with chromosome 17q24-q25 short tandem repeat (STR) markers in three HNA families and suggestive linkage was found in the other two HNA families. Analysis of the informative recombinations in affected individuals allowed us to reduce the HNA linkage interval to a candidate region of 3.5 cM.

Resolution of MRI abnormalities of the oculomotor nerve in childhood ophthalmoplegic migraine.

Ophthalmoplegic migraine is an uncommon disorder, usually starting in older childhood. Its physiopathology remains obscure and diagnosis is reliant on clinical grounds and exclusion of other disorders. We report four cases of childhood ophthalmoplegic migraine, one of them starting in infancy. Association with other types of migraine is common. Two of the three patients studied by magnetic resonance imaging (MRI) showed enhancement and enlargement of the cisternal portion of the oculomotor nerve, which spontaneously resolved after 2 and 4 years, respectively. Persistence of clinical recurrences was associated with long-lasting presence of the MRI finding, and possibly with mild sequelae. These radiological abnormalities suggest a common physiopathological mechanism with other inflammatory diseases, except for a benign evolution which, added to its specific anatomic site, seems to be the only neuroradiological marker, besides normality, in ophthalmoplegic migraine. The very long potential duration of MRI changes and the scarcity of clinical episodes make feasible its incident discovery once the migraine attack has become a remote memory.

[Profile of the patient who drops out of neuropediatric follow-up]. / Perfil del paciente que abandona el seguimiento neuropediátrico.

INTRODUCTION: Patients who drop out of programmed follow-up cause adverse effects to both themselves and the running of the medical. OBJECTIVE: To obtain information which would permit us to modify guidelines for medical care in cases with particular diagnoses, so as to avoid interrupting follow-up. PATIENTS AND METHODS: We selected all the patients who attended during 1995, and on 31 December 1995 had not been discharged or died. We considered a patient to have dropped out of follow-up when there was failure to attend the centre during two consecutive years without a justifiable reason. Logistic regression analysis was used to determine the profile of the patients who dropped out of follow-up. RESULTS: Of the patients attended during one year and whose treatment should have been continued, 16% dropped out; 70% of those who dropped out of their follow-up treatment were somewhat older than the rest and came in particular from two of the five health districts of the province. They had tics, tension headaches and migraine. Only three independent factors are associated with dropping out: absence of complementary tests, which is favorable, and epilepsy or previous long-term follow-up which is unfavorable. CONCLUSION: Reduction in the programmed follow-up of patients with conditions which do not require complementary tests may reduce the drop out rate and improve the functioning of the Neuropaediatric Clinic.

[Etiology of epilepsy in adolescents]. / Etiología de las epilepsias del adolescente.

OBJECTIVE: To review the etiology of epilepsies in adolescent patients treated at the Child Neurology Clinic, during the years 1995-1997. PATIENTS AND METHODS: All 13 years old patients, or older, were selected and considered adolescents. RESULTS AND CONCLUSIONS: A total of 863 patients with epileptic seizures were reviewed. Among them, 225 were epileptic adolescents and another 8 were adolescents with a single seizure or with several seizures clustering into a single event. Among the former, 163 suffered from partial epilepsy and 62 from generalized epilepsy. Partial epilepsies were distributed as: idiopathic (69), remote symptomatic (49) and cryptogenic (45). Generalized epilepsies were: idiopathic (22), cryptogenic (16) and cryptogenic-remote symptomatic (24). The latter included the Lennox-Gastaut syndrome, West syndrome, polymorphic epilepsy, etc. The etiology of these patients and related literature are reviewed in order to study the proper nosologic location of these entities.

[Telephone consultation in child neurology practice: quantification and contents]. / Labor asistencial telefónica en la consulta neuropediátrica: cuantificación y contenido.

INTRODUCTION: The workload of telephone consultations has been scarcely studied except at the Emergency Units, in spite of the considerable amount of time consumed by the task in normal practice. OBJECTIVE: To asses the workload of telephone consultations in a Neuropediatric Unit, during normal working hours. METHODS: A prospective analysis of all calls received during a year, at the out-patient hospital-based neuropediatric clinic. RESULTS: 150-200 telephone consultations were received every month, decreasing during the holiday seasons. They amount to two thirds of the face-to-face contacts at the clinic, during the same period of time, and require about 10% of our day-time working hours. Disorders more likely to produce the calls: epilepsy (40%), mental retardation (19%), cerebral palsy (11%), all others with a frequency lower than 5%. These percentages, and those of hydrocephalus, autism and spina bifida, are similar to those encountered in normal practice, while headaches, speech delay, hyperactivity, syncopes, etc. produced half the number of calls expected; myopathies doubled the number of calls expected. The monthly frequency of calls varied significatively, along the year, for epilepsy, mental retardation, hyperactivity, migraine and autism. Calls were made especially by the family (49%), but it depends of the purpose and the patient's diagnosis. The purpose was most frequently to consult about the symptomatology of the illness; treatments produced 7% of calls; and discussion about citations, 19.5%, regardless of the diagnosis. CONCLUSION: In neuropediatric practice, telephone consultations should be recognized and provided for in order to manage effectively the clinical demand.

[Neuropediatric clinical practice in a tertiary hospital of Basque Country]. / La práctica clínica neuropediátrica en un hospital terciario del País Vasco.

INTRODUCTION: In our country, studies on the neuropediatric practice are scarce, in spite of their importance for planning of spending and resources, and definition of quality criteria. OBJECTIVE: To study the clinical workload of the main neuropediatric clinical problems. METHODS: Prospective, longitudinal, descriptive study of doctor-patient encounters, according to diagnosis, in the Child Neurology Division of a tertiaty hospital. RESULTS: 3,200 visits, of which 83% were ambulatory. 24 ambulatory visits per 1,000 inhabitants younger than 15 years, and year. Diagnosis demanding larger clinical activity for out-patients were: epilepsy/seizures (38%), mental retardation (17%), headaches (17%), hyperactivity/conduct disorders (12%), and cerebral palsy/permanent motor sequela (10%). Among in-patients: epilepsy/seizures (47%), mental retardation (10%), brain tumors/neurological complications of oncology disorders (8%), cerebral palsy/motor sequela (8%), and neurological complications of prematurity (7%). Among new out-patients, headaches is the most frequent diagnosis, followed by epilepsy; among new in-patients, epilepsy holds the first place, followed by neurological complications of prematurity and brain trauma. The index follow-up/first visit is much larger for the real neurologic patient than for functional disorders so frequent among new referrals. CONCLUSIONS: The neuropediatric practice comprises essentially epilepsy, cognitive and conduct disorders, and headaches. Unfortunately, our practice is in part being defined by the pressure exerted by the primary medical care and by hospital management practices.

[Long-term follow-up of childhood epilepsy treated with vigabatrin outside of clinical trials]. / Seguimiento a largo plazo de la epilepsia infantil tratada con vigabatrina, fuera de los ensayos clínicos.

INTRODUCTION: Experimental conditions are not mirrored by clinical practice. OBJECTIVE: To study the efficacy of vigabatrin in the usual conditions of everyday clinical practice. PATIENTS AND METHODS: Retrospective review of all epileptic patients treated with vigabatrin in a neuropediatric outpatient clinic. OUTCOME MEASURES: a) Persistent seizure frequency reduction > or = 50%, and total control of seizures. Potential predictors of response were studied by logistic regression. b) Duration of VGB therapy, studied by the Kaplan-Meier method and its associated log-rank test. RESULTS: 113 patients with: partial symptomatic epilepsy (38%), partial cryptogenic (25.6%), partial idiopathic (6%), West syndrome (14%), Lennox-Gastaut syndrome (6%), other syndromes (9.7%). Reduction of seizure frequency was attained by 60% of patients at 3 months, sustained during 12 months by 40%, and during 5 years by 14%. Total control of seizures was present in 33% of patients at 3 months, persisted 12 months in 18% and 5 years in 2%. Independent predictors of a poor outcome were generalized seizures (except infantile spasms) and cerebral palsy, among others. The probability of continuing vigabatrin (VGB) therapy was 78% at 6 months, 55% at 2 years and 32% at 5 years. Duration of therapy was modified by early therapeutic response and antecedent of status epilepticus, among others. Adverse events were recorded in 18.5%. Visual fields were not studied in these series. CONCLUSIONS: For the time being, VGB-treated patients belong to the difficult-to-treat group. Percentages of responders depend upon duration of follow-up.

[Opercular epileptic syndrome: an unusual form of benign partial epilepsy in childhood]. / El síndrome opercular epiléptico: una forma peculiar de epilepsia parcial benigna de la infancia con paroxismos rolándicos.

INTRODUCTION: Functional opercular syndrome in childhood is an exceptional form of presentation of benign partial epilepsy with centro-temporal rolandic spikes (BECRS). CLINICAL CASES: We studied the evolution of four patients, three of them followed for more than 15 years. Two were siblings, and their father suffered from BECRS with permanent language problems (verbal dyspraxia) and difficulty of protunding his tongue in adulthood. A third patient suffered benign familial neonatal convulsions (BFNC). In all four patients the actual illness begun as a BECRS with opercular troubles as an ictal phenomena. At about four years of age, the opercular disfunction became evident, with severe drooling, facial hypomobility and speech disturbance which waxed and vanished along weeks, months or years, apparently not ictal. Antiepileptic drugs not only were unable to control this situation but also, some of them, like carbamazepine, even worsened the opercular disfunction, increased the number of seizures and enhanced the neuropsychologic disfunction. Only clobazam could achieve the control on opercular disfunction. After 16 years, no further treatment was needed for all patients. There were some permanent sequelae, as speech and orolingual dyspraxia and different neuropsychologic problems. CONCLUSION: Of noteworth the best performance was attained by the patient treated with clobazam on monotherapy.

[Therapeutic failure, treatment and non-treatment of childhood epilepsy]. / Fracaso terapéutico, tratamiento y no tratamiento de la epilepsia infantil.

INTRODUCTION: The classification of epileptic syndromes defines the prognosis and offers some orientation about treatment in childhood epilepsy. OBJECTIVE: To study the medical therapy according to epileptic syndromes in the everyday practice of a hospital based outpatient neuropediatric clinic. METHODS: Survey of the database using an algorithm to define therapeutic failure, treatment and spontaneous evolution, according to syndrome and drug, of all epileptic patients attended at the clinic during 1966. RESULTS: 465 patients with: monotherapy 38%, politherapy 20%, therapeutic success (follow-up after drug discontinuation) 21%, spontaneous evolution 22% (54% of partial idiopathic epilepsies). Most used antiepileptic drugs (VPA > CBZ > VGB > CLB > PB > PHT > LTG > ESM > PRM > GBT) are those with lowest failure rate and highest percentage of patients on monotherapy. Percentages of monotherapy in treated patients and of previous failure out of total number of patients are: idiopathic partial epilepsies: 85% and 10%; remote symptomatic partial: 58% and 43%; cryptogenic partial: 53% and 50%; idiopathic generalized: 83% and 25%; symptomatic-cryptogenic generalized: 34% and 63%; undetermined: 45% and 43%. CONCLUSIONS: Screening of the database serves as a quality control but the use of an algorithm offers only an approximation to reality. In idiopathic partial epilepsy treatment can be avoided in half of the patients and failure is lowest for VPA and CBZ. In idiopathic generalized epilepsies VPA predominance is almost absolute with a very low failure rate. In all other epileptic syndromes the therapeutic failure rate is about 50% regardless of drug, except for VPA which shows a moderately better outcome.

Antiepileptic drugs and atypical evolution of idiopathic partial epilepsy.

Six patients with classic benign epilepsy of childhood with centrotemporal spikes, treated with carbamazepine (four patients) or sodium valproate (two patients) evolved atypically because the epileptic disorder, diffusion of the electroencephalographic (EEG) discharges during wakefulness, and continuous spike-and-wave during slow sleep associated with severe neuropsychologic abnormalities worsened. These features appeared after a seizure-free interval varying for 2 weeks to 1 year 6 months after initiating therapy and remitted when the previous anticonvulsant drug was discontinued and either substituted with another drug or the patient was left without any treatment. Once the initial antiepileptic drug was discontinued and after a period roughly proportional to the duration of the clinical-EEG complication, the evolution of the patients' seizures was not unusual for this type of epilepsy, with patients eventually becoming free of both seizures and medication and reaching normal school achievement. The clinical complications cannot be attributed solely to the drugs. It must also be related to the underlying substract (i.e., the specific epileptic syndrome involved) that in some patients becomes susceptible to atypical evolution when either product is administered.

Reversible endocrine dysfunction and pituitary stalk enlargement.

We report 4 patients (3 of which were children) with diabetes insipidus and different degrees of hypopituitarism in whom a pituitary stalk enlargement was disclosed on imaging techniques, and in whom radiological and functional recovery was observed during follow-up. Pituitary substitution therapy with desmopressin, thyroxine, hydrocortisone, growth hormone and/or oral contraceptives was prescribed. During follow-up, regression of the stalk lesion was seen which was spontaneous in 2 cases, following a short course of corticosteroids in another and an empirical trial of tuberculostatic drugs in the fourth. A partial recovery of pituitary function was also observed. These cases illustrate that pituitary stalk enlargement and associated hypopituitarism may be reversible; however, this morphological and functional recovery has rarely been described in adults and has not been previously reported in children.