Sharon Samueli

Impaired oligodendroglial turnover is associated with myelin pathology in Focal Cortical Dysplasia and Tuberous Sclerosis Complex

Conventional antiepileptic drugs suppress the excessive firing of neurons during seizures. In drug‐resistant patients, treatment failure indicates an alternative important epileptogenic trigger. Two epilepsy‐associated pathologies show myelin deficiencies in seizure‐related brain regions: Focal Cortical Dysplasia IIB (FCD) and cortical tubers in Tuberous Sclerosis Complex (TSC). Studies uncovering white matter‐pathology mechanisms are therefore urgently needed to gain more insight into epileptogenesis, the propensity to maintain seizures, and their associated comorbidities such as cognitive defects. We analyzed epilepsy surgery specimens of FCD IIB (n = 22), TSC (n = 8), and other malformations of cortical development MCD (n = 12), and compared them to autopsy and biopsy cases (n = 15). The entire lesional pathology was assessed using digital immunohistochemistry, immunofluorescence and western blotting for oligodendroglial lineage, myelin and mTOR markers, and findings were correlated to clinical parameters. White matter pathology with depleted myelin and oligodendroglia were found in 50% of FCD IIB and 62% of TSC cases. Other MCDs had either a normal content or even showed reactive oligodendrolial hyperplasia. Furthermore, myelin deficiency was associated with increased mTOR expression and the lower amount of oligodendroglia was linked with their precursor cells (PDGFRa). The relative duration of epilepsy (normalized to age) also correlated positively to mTOR activation and negatively to myelination. Decreased content of oligodendroglia and missing precursor cells indicated insufficient oligodendroglial development, probably mediated by mTOR, which may ultimately lead to severe myelin loss. In terms of disease management, an early and targeted treatment could restore normal myelin development and, therefore, alter seizure threshold and improve cognitive outcome.

Tuberous Sclerosis Complex: new criteria for diagnostic work-up and management

SummaryTuberous sclerosis complex (TSC) is a rare genetic multisystem disorder, characterized by predominantly benign tumors in potentially all organ systems. System involvement, severity of clinical symptoms and the response to treatment are age-dependent and heterogeneous. Consequently, the disorder is still not recognized in a considerable number of patients. The diagnostic criteria and the guidelines for surveillance and management of patients with TSC were revised, and the establishment of specialized TSC-centers was strongly recommended during an International Consensus Conference in 2012. TOSCA (TuberOus SClerosis registry to increase disease Awareness), an international patient registry, was started to allow new insights into the causes of different courses. Finally, there are—since the approval of the mTOR inhibitor Everolimus—promising new therapeutic approaches.This review focuses on the various TSC related symptoms occurring at different ages, the novel recommendations for diagnosis and treatment as well as the need for multidisciplinary follow-up.ZusammenfassungDie Tuberöse Sklerose (TS) ist eine seltene, genetisch bedingte Multisystemerkrankung, die zu (vorwiegend) benignen Tumoren in nahezu allen Organsystemen führen kann. Sowohl Ausprägung und Schweregrad der klinischen Symptome als auch das Ansprechen auf therapeutische Interventionen sind altersabhängig und zudem individuell äußerst heterogen. Es wird daher angenommen, dass viele Betroffene spät oder gar nicht erkannt werden.2012 wurden im Rahmen einer internationalen Konsensus Konferenz die diagnostischen Kriterien, sowie die Richtlinien für Therapie und Überwachung überarbeitet und die Etablierung spezialisierter multidisziplinärer TS-Zentren dringend empfohlen. Mit TOSCA (TuberOus SClerosis registry to increase disease Awareness) wurde zudem ein internationales Patienten-Register geschaffen, das neue Erkenntnisse über die Ursachen unterschiedlicher Ausprägung und Verläufe der Erkrankung ermöglichen soll. Seit der Zulassung des mTOR-Inhibitors Everolimus 2011 ist nun erstmals eine spezifische Multisystem-Therapie verfügbar. Der folgende Review Artikel gibt einen umfassenden Überblick über die verschiedenen Symptome und präsentiert die rezenten Neuerungen bezüglich Diagnostik, Therapie und Verlaufsbeobachtung.

The ketogenic diet in infants – Advantages of early use

OBJECTIVE To evaluate the efficacy and safety of the ketogenic diet (KD) in infants (< 1.5 years of age) compared with older children. METHODS Patients with complete follow-up data of ≥ 3 months after initiation of the KD were analyzed retrospectively. Infants < 1.5 years at initiation of the KD (Group A) were compared with children > 1.5 years (Group B). RESULTS 127 children were screened, 115 (Group A: 58/Group B: 57) were included. There were no significant differences between groups with respect to responder rates (63.8% vs. 57.9% at 3 months), but more infants became seizure free (34.5% vs. 19% at 3 months; 32.7% vs. 17.5% at 6 and 12 months). This result remained stable also after termination of the KD (30.6% vs. 3.9% at last follow-up) (p = 0.000). Looking at infants < 9 months of age separately (n = 42), this result was even stronger with significantly more infants being seizure free at 6 and at 12 months (p = 0.005, p = 0.014, respectively). In addition, a significantly higher number of infants remained seizure free in the long-term (p = 0.001). No group differences between infants and children with respect to safety were observed. Overall 52/115 patients (45.21%) reported side effects, but withdrawal of the KD was only necessary in one infant. Acceptance of the KD was better in infants compared with children at 3 months (0 vs. 14, p = 0.000), but became difficult when solid food was introduced (16 vs. 14; n.s.). SIGNIFICANCE According to our results, the KD is highly effective and well tolerated in infants with epilepsy. Seizure freedom is more often achieved and maintained in infants. Acceptance of the diet is better before the introduction of solid food. Therefore, we recommend the early use of the KD during the course of epilepsy.

Ketogenic parenteral nutrition in 17 pediatric patients with epilepsy

Ketogenic parenteral nutrition (kPN) is indicated when enteral intake is temporarily limited or impossible, but evidence‐based prescriptions are lacking. Objective was to evaluate the efficacy and safety of kPN in children with epileptic encephalopathies using a new computer‐based algorithm for accurate component calculating.

Everolimus in infants with tuberous sclerosis complex-related West syndrome: First results from a single-center prospective observational study

Tuberous sclerosis complex (TSC) is the most common cause of West syndrome (WS). Currently available treatment options are ineffective in the majority of affected infants and/or associated with potential serious side effects. Based on the assumption that mTOR overactivation results in increased neuroexcitability in TSC, mTOR inhibitors have been studied as antiseizure therapy. As a result, everolimus recently received approval for the adjunctive treatment of patients aged ≥2 years with refractory TSC‐associated focal and secondary generalized seizures. However, efficacy and safety data for infants with TSC‐associated WS are still lacking. Therefore, a prospective open‐label observational study was initiated at our center, to evaluate everolimus add‐on treatment in infants with TSC‐associated WS, previously refractory to standard treatment. For this preliminary report, data from four male infants with TSC2 and a median observation period of 13 (range = 8‐42) months after treatment initiation were analyzed. Two infants showed electroclinical remission until day 14 after everolimus treatment initiation. In one additional infant, hypsarrhythmia resolved. No relapse after initial response was documented. Developmental progress improved in three infants. Tolerability was similar to that described in older children. According to our preliminary results, everolimus appears to have the potential to treat successfully both spasms and hypsarrhythmia in infants with TSC‐associated WS, contributing to better developmental progress.

PP01.13 – 2471: Sturge-Weber syndrome is associated with complex malformations of cortical development – A case report

We present an 11 months old girl with Sturge Weber syndrom (SWS) and infantile spasms, refractory to treatment; The child was delivered in the 36th week of gestation. On prenatal ultrasound the obstetrician noticed an enlargement of the right ventricle. Postnatal, the MRI showed at first indications for an early SWS; hypertrophy of the right hemisphere with reduced gyration, T1 hyperintense and Tw2 hypointense signal alterations in the right periventricular white matter; proliferation of superficial vessels after administration of contrast agent and on SWI sequences, and a dysplastic corpus callosum. From day 1 onwards the child presented with a severe muscular hypotonia and daily series of complex partial and focal seizures occurred. The EEG was concordant with continuous epileptic discharges over the right hemisphere. The establishment of several AEDs did not yield any seizure control. Extensive diagnostics were carried out and in the light of these results the suspicious diagnosis of a type III SWS with an isolated leptomeningeal-brain angiom, was raised. In the combination of the diagnostics and the patients poor general condition, the indication for epilepsy surgery was met. At the age of 7 months a functional hemispherotomy was performed. Since the surgery the patient is seizure-free and there is a significant improvement of motor skills, despite the expected left-sided hemiparesis. Neurohistopathological assessment of the resected tissue showed severe meningoangiomatosis associated with classical 4-layered polymicrogyria, although no mosaic mutation in the GNAQ gene was found. Detailed immunohistological analysis presented small immature neurons in a 4-layered cortical organization as well as various sizes of malformed bloodvessels within the meninges. In addition, a hyperactivation of the (PI3K)-AKT3-mTOR pathway (pS6, pAkt Ser 473) could be detected. Our case highlights the importance of thorough clinical assessment and the effect of epilepsy surgery also in highly complex malformations of cortical development.

OP53 – 2462: The role of mTOR inhibitors in TSC associated epilepsy

We evaluated prospectively the effect of Everolimus on epilepsy in children and adolescents with TSC treated with Everolimus for SEGA at our center. Methods This is a retrospective analysis of prospectively collected data: included were patients ≤19 years with epilepsy, treated with Votubia, who had regular prospective follow-up every 3 months at the study center (clinical inspection and EEG, seizure diaries, blood sampling). Everolimus is orally administered once per day, starting with 4.5 mg/m 2 and titration to achieve blood trough concentrations of 5–15 ng/ml. Response was defined as ≥50% reduction in seizure count. Results We present pilot data of 12 patients (4 female, 8 male), with genetically confirmed diagnosis of TSC (3 TSC1, 9 TSC2 mutations). The median age at initiation of Votubia was 10 years (y) (range: 2–19 y). The median duration of epilepsy prior to treatment was 9.5 y (range: 1.75–16.75 y). The median number of AEDs prior to treatment was 1 (range: 1–3). The median seizure frequency prior to treatment was 30 seizures/month (range: 2–1470 seizures/month). 8/12 (66%) patients were responders. The median follow up after initiation of Everolimus was 13.5 months (range: 2–31 months). The median reduction in seizure frequency was 93% (range: 0–100%). Four patients became seizure free. The median number of AED after treatment was 1 (range: 1–2). The effect on seizure frequency was accompanied by significant developmental progress in all seizure free children. 4 patients were non-responders, one of them was incompliant. Side effects were observed in 7 patients (58%). The most common side effects were aphtae (7/7); 1 patient was hospitalized because of angina herpetica and pneumonia. In no case the Everolimus treatment had to be interrupted or withdrawn. Conclusions Everolimus seems to be effective and safe in treating TSC associated epilepsy in pediatric patients (even in cases prior refractory to AEDs).

OP52 – 2694: The ketogenic diet versus ACTH in the treatment of infantile spasms: A prospective randomised study

Objective The prognosis of infantile spasms (IS) is usually unfavorable with respect to treatment and developmental outcomes. The antiepileptic drugs (AEDs) most likely to be effective in the short-term management (complete cessation of spasm and EEG normalization) are ACTH and Vigabatrin, but there is insufficient evidence that these drugs also improve long-term outcomes. Both drugs have shown serious (irreversible and in part lethal) side effects. The ketogenic diet (KD) is licensed for drug-resistant epilepsy including IS as second-line treatment. Aim of this randomized, prospective study was to evaluate the efficacy and tolerability of the KD compared with ACTH. Methods All infants with IS referred to the Medical University of Vienna between June 2008 and September 2014 who were eligible for both treatments were included and randomized to either ACTH or the KD (liquid formula) after informed consent. When failure to the first treatment occurred (seizures and/or persistent hypsarrhyhtmia), patients were switched to the alternative treatment. Seizure and developmental outcomes as well as side effects were evaluated at 12 months after treatment initiation. Results 32 children were randomized (16 ACTH/16 KD). 9/16 randomized to the KD became seizure free (56%), with recurrence of seizures in 3 (18%) after 6 months. 7 (44%) did not respond. 10 non-responders were then switched to ACTH and further 4 children became seizure free (40%). The KD was well tolerated. 10/16 patients randomized to ACTH (62%) became seizure free and 3 (18%) relapsed, 6 (38%) did not respond. 6 patients were then switched to the KD and one child became seizure free (16%). 14/16 children on ACTH children showed severe side effects. Conclusion No differences in responder rates or in efficacy were observed between the KD and ACTH. However, compliance was better in the KD group and no severe side effects were observed.