Shared Decision Making and Disease Modifying Therapy in Families of Children and Adolescents with Pediatric Onset Multiple Sclerosis.

BACKGROUND: Deciding on a disease modifying therapy (DMT) for the treatment of pediatric onset multiple sclerosis (POMS) often presents a challenge to families. Parents are often overwhelmed by DMT choices, but they desire to be an integral part of the decision making process for their child. There is no standard approach for how best to involve families in this process. The aim of this study was to describe the experience of decision making related to the use of disease modifying therapy in parents of children and adolescents with POMS. METHODS: The research aim was addressed using a descriptive survey design. Participants were recruited from the Pediatric MS and Related Disorders Program at Boston Children's Hospital as well as from the Pediatric Multiple Sclerosis Alliance online Facebook group. RESULTS: Overall, fewer than half of parents felt very satisfied with the DMT they chose for their child with POMS (44%). Parental satisfaction with the decision making process increased with a high level of control of the process (p < 0.0001), satisfaction with communication (p < 0.0001), and feeling supported by the healthcare provider (p < 0.0001). PRACTICE IMPLICATIONS: Healthcare providers should recognize the importance of the role of the family in the decision making process and how this directly impacts health outcomes. An open discussion at the time of DMT education should involve identification of family values and preferences. The use of online decision support tools have a valuable role in determining family preferences. CONCLUSION: There is an opportunity of healthcare providers to foster shared decision making practices to improve satisfaction among parents of children and adolescents with POMS. Healthcare providers should work closely with families to identify and incorporate their personal preferences for their role in the decision making process. Future research should include the testing of decision support tools for decision making in POMS.

IQ predictors in pediatric opsoclonus myoclonus syndrome: a large international cohort study.

AIM: To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD: In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (<-2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike's information criterion was performed to understand the relationship between exposures and FSIQ. RESULTS: Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40-114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow-up (p<0.001) predicted FSIQ (adjusted R2 =0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse. INTERPRETATION: Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes.

Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing.

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome due to germline mutations in either TSC1 or TSC2. 10-15% of TSC individuals have no mutation identified (NMI) after thorough conventional molecular diagnostic assessment. 53 TSC subjects who were NMI were studied using next generation sequencing to search for mutations in these genes. Blood/saliva DNA including parental samples were available from all subjects, and skin tumor biopsy DNA was available from six subjects. We identified mutations in 45 of 53 subjects (85%). Mosaicism was observed in the majority (26 of 45, 58%), and intronic mutations were also unusually common, seen in 18 of 45 subjects (40%). Seventeen (38%) mutations were seen at an allele frequency < 5%, five at an allele frequency < 1%, and two were identified in skin tumor biopsies only, and were not seen at appreciable frequency in blood or saliva DNA. These findings illuminate the extent of mosaicism in TSC, indicate the importance of full gene coverage and next generation sequencing for mutation detection, show that analysis of TSC-related tumors can increase the mutation detection rate, indicate that it is not likely that a third TSC gene exists, and enable provision of genetic counseling to the substantial population of TSC individuals who are currently NMI.

Localization of the epileptogenic foci in tuberous sclerosis complex: a pediatric case report.

Tuberous sclerosis complex (TSC) is a rare disorder of tissue growth and differentiation, characterized by benign hamartomas in the brain and other organs. Up to 90% of TSC patients develop epilepsy and 50% become medically intractable requiring resective surgery. The surgical outcome of TSC patients depends on the accurate identification of the epileptogenic zone consisting of tubers and the surrounding epileptogenic tissue. There is conflicting evidence whether the epileptogenic zone is in the tuber itself or in abnormally developed surrounding cortex. Here, we report the localization of the epileptiform activity among the many cortical tubers in a 4-year-old patient with TSC-related refractory epilepsy undergoing magnetoencephalography (MEG), electroencephalography (EEG), and diffusion tensor imaging (DTI). For MEG, we used a prototype system that offers higher spatial resolution and sensitivity compared to the conventional adult systems. The generators of interictal activity were localized using both EEG and MEG with equivalent current dipole (ECD) and minimum norm estimation (MNE) methods according to the current clinical standards. For DTI, we calculated four diffusion scalar parameters for the fibers passing through four ROIs defined: (i) at a large cortical tuber identified at the right quadrant, (ii) at the normal appearing tissue contralateral to the tuber, (iii) at the cluster formed by ECDs fitted at the peak of interictal spikes, and (iv) at the normal appearing tissue contralateral to the cluster. ECDs were consistently clustered at the vicinity of the large calcified cortical tuber. MNE and ECDs indicated epileptiform activity in the same areas. DTI analysis showed differences between the scalar values of the tracks passing through the tuber and the ECD cluster. In this illustrative case, we provide evidence from different neuroimaging modalities, which support the view that epileptiform activity may derive from abnormally developed tissue surrounding the tuber rather than the tuber itself.

Similar trends in serum VEGF-D levels and kidney angiomyolipoma responses with longer duration sirolimus treatment in adults with tuberous sclerosis.

CONTEXT: We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up. OBJECTIVE: To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus. SETTING: Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1). PATIENTS: There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients. MAIN OUTCOME MEASURE(S): We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups. RESULTS: At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787 ± 426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971 ± 4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p=0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed. TRIAL REGISTRATION: Clinical trials.gov NCT00126672.

Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation.

OBJECTIVE: The aim of the work described here was to systematically analyze the developmental trajectory of patients with tuberous sclerosis complex (TSC). METHODS: A retrospective longitudinal chart review was performed, selecting patients who received multiple neuropsychological assessments. Intellectual/Developmental Quotients, Adaptive Behavior Composite scores, and clinical data were collected. On available EEGs, interictal epileptiform discharges were counted. RESULTS: Sixty-six (18%) patients with TSC received multiple cognitive and adaptive development assessments. The mean intelligence of this study group remained relatively stable, albeit variable. Significant decline in adaptive functioning was observed, associated with lower age at seizure onset. Patients who underwent neurosurgery prior to baseline testing showed cognitive improvement. Developmental declines were significantly associated with increased numbers of antiepileptic drugs, with a trend toward association with mutation type and interictal epileptiform discharges. CONCLUSION: This study suggests that the developmental course of patients with TSC may be altered by epilepsy comorbidity and neurosurgery, underlining the need for early and effective interventions in this population.

Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.

BACKGROUND: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. METHODS: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. RESULTS: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). CONCLUSIONS: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. TRIAL REGISTRATION: Clinicaltrials.gov NCT00126672.

Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome caused by mutations in TSC1 and TSC2. However, 10-15% TSC patients have no mutation identified with conventional molecular diagnostic studies. We used the ultra-deep pyrosequencing technique of 454 Sequencing to search for mosaicism in 38 TSC patients who had no TSC1 or TSC2 mutation identified by conventional methods. Two TSC2 mutations were identified, each at 5.3% read frequency in different patients, consistent with mosaicism. Both mosaic mutations were confirmed by several methods. Five of 38 samples were found to have heterozygous non-mosaic mutations, which had been missed in earlier analyses. Several other possible low-frequency mosaic mutations were identified by deep sequencing, but were discarded as artifacts by secondary studies. The low frequency of detection of mosaic mutations, two (6%) of 33, suggests that the majority of TSC patients who have no mutation identified are not due to mosaicism, but rather other causes, which remain to be determined. These findings indicate the ability of deep sequencing, coupled with secondary confirmatory analyses, to detect low-frequency mosaic mutations.

The natural history of epilepsy in tuberous sclerosis complex.

BACKGROUND: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. METHODS: A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. RESULTS: Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission. CONCLUSION: Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome.

Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile.

PURPOSE: To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies. METHODS: Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB. RESULTS: Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p < 0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency >50%) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p < 0.027) and longer total time on VGB (p < 0.045) was associated with better IQ-developmental quotient (DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52%. VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings. CONCLUSION: We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.

Potenciales ligados a eventos y función cognitiva en senescentes / Event related potentials and cognitive function in senescents

Los potenciales ligados a eventos (PLE) se relacionan con diversos aspectos de la función cognitiva, el aumento de latencia de P300 con la edad refleja el enlentecimiento normal de funciones del sistema nervioso; este aumento se exagera en demencias de diversos origenes y en otros desórdenes cognitivos. Con objeto de determinar la relación entre función cognitiva, indicadores electrofisiológicos e indicadores neuropsicológicos, se estudió a 40 sujetos mayores de 60 años (9 hombre y 31 mujeres, edad promedio 71 años). Se aplicó Mini Mental State Examination de Folstein (MMSE) (x 25,7), escala de inteligencia de Wechsler para adultos (WAIS) con subescalas de memoria (x 88,1) y C.I. total (x 85,4). Los sujetos fueron entrevistados por un psiquiatra, quien, ignorando los resultados de los instrumentos antes mencionados, diagnosticó según ICD-10: 13 personas sanas, 8 con trastorno mental orgánico, 3 con trastornos debidos al consumo de alcohol, 11 con trastorno del humor, 5 con trastornos neuróticos y 5 con retraso mental. Además se registró potencial evocado auditivo ligado a eventos (cognitivo, P300) mediante paradigma "Odd-Ball" en tareas tiempo de reacción (x lat P300 364,9 ms) y cómputo mental (x lat P300 369,7 ms). En el grupo diagnóstico "trastorno mental orgánico" hay una significativa mayor proporción de sujetos que no presentan onda P300. Hubo correlación entre latencia de P2 y puntajes de memoria del WISC y MMSE (Spearman, 0,39 y 0,47 respectivamente). El análisis de varianza no paramétrico (Kruskal y Wallis) fue significativo para MMSE y WAIS en relación al diagnóstico psiquiátrico. Se concluye que hubo relación entre los diferentes indicadores y el estado cognitivo de los sujetos estudiados. Se plantea la necesidad de ampliar los estudios relacionados a latencia de P2 y menoria

Effects of stimulation intensity, gender and handedness upon auditory evoked potentials

Los sujetos zurdos y de sexo femenino tienden a exhibir menores grados de asimetria anatômica, mayores diâmetros del cuerpo calloso y mayor representación bilateral de funciones específicas. Los componentes sensoriales y cognitivos del potencial evocado auditivo (PEA) cortical han demostrado sensibilidad a la intensidad de estimulación y asimetria en sujetos masculinos. En este estudio se investiga la influencia de sexo, manualidad e intensidade de la estimulación sobre los componentes corticales del PEA. 56 sujetos voluntarios fueron sometidos a estimulación auditiva (series de 100 clicks binaurales, duración de 1 mseg, frecuencia de 1/seg, a cuatro diferentes intensidades) instruyéndoseles a prestar atención pasiva. Se registró derivaciones Cz, C3 y C4 referidas a mastoides bilateral obtenidos sobre 100 clicks. La intensidad de la derivación central. La asimetria sólo es influenciada por la amnualidad; los Ss diestros exhiben mayores amplitudes P1N1 en el hemisferio derecho

Componentes positivos tardios (CPT) del potencial evocado auditivo (PEA) cortical y demanda atencional / Late positive components of auditory evoked potencial and attentional demand

Con objeto de estudar la influencia de la demanda atencional sobre los CPT auditivos se registró PEA de 10 hombres y 10 mujeres voluntarios entre 18 y 35 anos en 3 condiciones : atención pasiva (AP), tarea de tiempo de reacción (TR) cómputo mental (C) de los estímulos infrecuentes. Se administró 3 bloques de 400 tonos binaurales (60 ms, 80 dB, intervalo interestímulo = 2 seg.) con 80 por ciento de 750 Hz (frecuentes = EI) y 20 por ciento de 1500 Hz (infrecuentes = EI) randomizados. Se registró Pz y Cz referidos a mastoides bilateral, tiempo de registro = 710 ms, se promedió 320 EI y 80 EI en cada condición. Se midió latencia de N1, P2, N2 y P300 y amplitud peak to peak mediante programa cursor manual. La amplitud de todos los componentes fué mayor en Cz que en Pz, las latencias fueron similares en ambas derivaciones. N2 y P300 aparecen con significativa mayor frequencia en EI de tareas con demanda atencional (TR y C), P2 y N2 acortan su latencia en las mismas condiciones y la amplitud N1P2 aumenta. La amplitud N2P3 y N1P3 es mayor en TR. La demanda atencional produce cambios en los componentes ligados a eventos, produciendo la aparición del componente P300 y parece ser mayor en la tarea de tiempo de reacción

El constructo esperanza: objetivación mediante indicadores verbales / The construct hope: objectivation through verbal indicators

Se ilustran brevemente los pasos a seguir en el desarrollo de una escala de análisis de contenido verbal según Gottschalk a través del ejemplo proporcionado por la Escala de Esperanza. Se presenta la traducción de la escala original junto a datos que demuestran que los puntajes de esperanza exhibidos por una muestra de estudiantes no se correlacionan con puntajes de Beck, Zung o EPQ. La publicación persigue subrayar la utilidad heurística de constructos teóricos descriptivos basados en referentes empíricos observables. Se hace hincapié en la relevancia de claves verbales de comunicaciones lingüísticas espontáneas en la operacionalización de variables psicológicas