Perampanel as precision therapy in rare genetic epilepsies.

OBJECTIVE: Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy. METHODS: This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified. RESULTS: A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months-8 years). Sixty-two patients (44.9%) were treated for >2 years. Ninety-eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity. SIGNIFICANCE: Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.

Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic hormone for infantile spasms: A single-center parallel-cohort randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of the ketogenic diet (KD) with standard adrenocorticotropic hormone (ACTH) treatment in infants with West syndrome. METHODS: In this parallel-cohort (PC) randomized controlled trial (RCT), infants were randomly allocated to KD or high-dose ACTH. Those who could not be randomized were followed in a PC. Primary end point was electroclinical remission at day 28. Secondary end points were time to electroclinical remission, relapse after initial response, seizure freedom at last follow-up, adverse effects, and developmental progress. RESULTS: One hundred one infants were included: 32 in the RCT (16 KD; 16 ACTH) and 69 in the PC (37 KD; 32 ACTH). Electroclinical remission at day 28 was similar between KD and ACTH (RCT: 62% vs 69%; PC: 41% vs 38%; combined cohort: 47% vs 48%; KD vs ACTH, respectively). In the combined cohort, time to electroclinical remission was similar between both treatments (14 days for KD, 16 days for ACTH). However, relapse rates were 16% (KD) and 43% (ACTH, P = 0.09), and seizure freedom at last follow-up was 40% (KD) and 27% (ACTH, P = 0.18). Adverse effects needing acute medical intervention occurred more often with ACTH (30% with KD, 94% with ACTH, P < 0.001). Age-appropriate psychomotor development and adaptive behavior were similar. Without prior vigabatrin (VGB) treatment, remission at day 28 was 47% (KD) and 80% (ACTH, P = 0.02); relapse rates were 29% (KD) and 56% (ACTH, P = 0.13). Consequently, seizure freedom at last follow-up was similar. In infants with prior VGB, seizure freedom at last follow-up was 48% (KD) and 21% (ACTH, P = 0.05). SIGNIFICANCE: The study is underpowered; therefore, its results should be interpreted with caution. KD is as effective as ACTH in the long term but is better tolerated. Without prior VGB treatment, ACTH remains the first choice to achieve short-term remission. However, with prior VGB, KD was at least as effective as ACTH in the short term and was associated with lower relapse rates in the long term; therefore, it represents an appropriate second-line treatment after VGB.

Pathophysiology of neurodevelopmental mTOR pathway-associated epileptic conditions: Current status of biomedical research.

Epilepsy is one of the most common and serious neurological disorders worldwide. It has no identifiable cause in approximately 50% of patients; in the other 50%, the condition may be due to a variety of etiologies and pathomechanisms. In this review, special focus is put on the prototypes of "mTORpathies": tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb. We review recent research data on mTORpathies, with emphasis on cortical tubers and FCD-like lesions (neuronal migration lines (NML)). A major pathologic aspect in the network of drug-resistant epilepsy progression is the limited myelination of the white matter observed in these lesions. Recently, an association between the myelin pathology and dysregulation of the mTOR signaling pathway was observed by several studies. The lowered myelin content was shown to correlate not only with an increased mTOR expression but also with the relative duration of epilepsy. Another recently published finding in surgical tissue from patients with drug-resistant epilepsy and malformations of cortical development is inflammation. Accumulating evidence reports persistent and complex activation of inflammatory pathways in both cortical tubers and FCD lesions. Due to the fact that cortical tubers, as well as FCD lesions, are highly epileptogenic, a possible link between chronic seizure activity and the occurrence of an inflammatory response observed within the dysplastic cortex was postulated. Previously, alterations in the levels of classical complement C1q-C3 molecules in experimental and human epilepsy have been reported, suggesting that the classical complement pathway may be a novel candidate mechanism for the underlying epileptogenic circuit mechanism.
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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.

Immediate termination of electrical status epilepticus in sleep after hemispherotomy is associated with significant progress in language development.

AIM: To study the effect of hemispherotomy on electrical status epilepticus in sleep (ESES) and language development. METHOD: Children with a confirmed diagnosis of ESES prior to surgery and a minimum of 24 months of developmental follow-up data were compared with age-matched controls without ESES. Language quotients (LQs) were calculated before and after surgery. RESULTS: Eleven patients (five females, six males) and 21 controls (11 females, 10 males) were included. Before surgery a significantly higher number of children in the study group (n=9) demonstrated severe developmental delay compared with children in the control group (n=13; p=0.015). In the study group ESES remitted immediately after surgery in 10 children, and a significant catch-up in LQs was observed in this group (preoperative mean 40.0 [standard deviation (SD) 22.2, interquartile range (IQR) 30.0-62.0]; postoperative mean 73.0 [SD 33.5, IQR 41.0-97.0]; p=0.037). There was no significant difference compared with controls at last follow-up after surgery (study group: five with severe impairment; control group: eight with severe impairment [p=0.971]). Overall, a favourable developmental outcome was associated with freedom from seizures (seizure-free group: median preoperative LQ 61.5, median postoperative LQ 78.0 [p=0.017]; seizure group: median preoperative LQ 35.5, median postoperative LQ 56.5 [p=0.273]) and antiepileptic drug withdrawal (off medication: median preoperative LQ 49.5, median postoperative LQ 78.0 [p=0.011]; on medication: median preoperative LQ 78.0, median postoperative LQ 83.5 [p=0.889]). INTERPRETATION: Children with ESES showed significantly lower preoperative language abilities than children without ESES. In cases with remission of ESES after surgery, marked improvement in LQs was noticed. This improvement cannot be fully explained by seizure-freedom alone as seizure-free children without preoperative ESES showed less improvement.

Corrigendum to "Expanding the phenotype of RBCK1-associated polyglucosan body myopathy type 1".

[This corrects the article DOI: 10.1016/j.ymgmr.2023.101031.].

Expanding the phenotype of RBCK1-associated polyglucosan body myopathy type 1.

Polyglucosan body myopathy-1 (PGBM1) is an extremely rare glycogen storage diseases that leads to muscle weakness and cardiomyopathy due to the accumulation of polyglucosan bodies. The clinical presentation appears to be partially dependent on the genetic mutation, but no clear genotype/phenotype correlation is currently possible. We describe a 7 year old patient, who initially presented with recurrent vomiting and respiratory infections until her first year of life. Diagnostic workup revealed an achalasia and the whole exome sequencing revealed an homozygous RBCK1 (RANBP2-type and C3HC4-type zinc finger containing 1) variant (c.896_899delAGTG) located in exon 7 (mid-domain), which has also been described in 4 patients with PGBM1. The unusual presentation with gastrointestinal and respiratory symptoms before the development of progressive muscle weakness expands the phenotype of this disease.

Impact of depressive symptoms on adverse effects in people with epilepsy on antiseizure medication therapy.

OBJECTIVE: We studied the impact of depressive symptoms on adverse effects (AEs) in people with epilepsy (PWE) on antiseizure medication (ASM) therapy. An effect of depression on the AE burden has already been reported. We studied the correlation of various depressive symptoms with specific AEs to assess which AEs are especially prone to being confounded by particular depressive symptoms. METHODS: PWE filled in a variety of questionnaires including the "Neurological Disorder Depression Inventory for Epilepsy" (NDDI-E), "Emotional Thermometers 4" (ET4) and "Liverpool Adverse Events Profile" (LAEP). Depression was defined by a NDDI-E score > 13. Depressive symptoms consisted of NDDI-E and ET4 items. Discriminant analysis identified those AEs (=LAEP items) that were most highly influenced by depression. Logistic regression analysis yielded correlations of different depressive symptoms with specific AEs. RESULTS: We included 432 PWE. The strongest discriminators for depression were the LAEP items "Depression", "Nervousness/agitation," and "Tiredness". Out of all depressive symptoms "Everything I do is a struggle" most strongly correlated with total LAEP score (odds ratio [OR] = 3.1) and correlated with all but one LAEP item. Other depressive symptoms correlated to varying degrees with total LAEP and item scores. The number of ASMs, lack of seizure remission, and female gender correlated with high LAEP scores. SIGNIFICANCE: To the best of our knowledge, we are the first to show that various depressive symptoms correlate with specific LAEP items. This information can be helpful for quick evaluation of whether the reporting of different LAEP items may be confounded by particular depressive symptoms. This is relevant because changes in therapy may differ depending on if AEs are confounded by depressive symptoms. Simply reporting a particular depressive symptom may give a clue to whether specific AEs are confounded by depression. Our findings confirm the importance of screening for depression in all PWE. PLAIN LANGUAGE SUMMARY: In this study we measured depressive disorder and side effects caused by medication used to treat epilepsy with self-reported questionnaires in a cohort of people with epilepsy. We found depressive disorder to influence the perception of side effects that are caused by drugs used to treat epilepsy. This knowledge can help to identify if the reporting of side effects is influenced by depression. Treating depression may help to reduce side effects and may thus increase the tolerability of anti-epileptic medication. People who tolerate their medication are more likely to take it and are thus less likely to develop epileptic seizure.

Vertical perithalamic hemispherotomy: a single-center experience in 40 pediatric patients with epilepsy.

PURPOSE: The current concept for hemispherotomy includes various lateral techniques and the vertical perithalamic hemispherotomy introduced by Delalande in 1992. We have chosen the vertical approach because of advantages that possibly influence outcome: the possibility to completely disconnect the hemisphere at the level of the thalamus obviating both the need to resect the insula and the need to open and dissect the subarachnoid space of the Sylvian fissure. METHODS: We retrospectively analyzed prospectively collected data of all patients who underwent vertical hemispherotomy at the Vienna pediatric epilepsy center. Seizure outcome was classified according to the International League Against Epilepsy (ILAE) proposal 2001. KEY FINDINGS: Follow-up data of 40 patients (22 male/18 female; median age 5.5 years; range 4.4 months to 20.1 years) were analyzed. Hemispherotomy was left in 26 and right in 14 patients. The underlying pathology was ischemic vascular in 19, malformation of cortical development (MCD) in 11, and other pathology in 10. No serious intraoperative complications were encountered. Only two infants (5.0%) needed blood replacement. There was one death on the fourth day after surgery caused by intractable hyponatremic brain edema. Three patients developed cerebrospinal fluid (CSF) disturbances, but only one needed a permanent ventriculoperitoneal (VP) shunt (2.5%). For outcome analysis we included 37 of 40 children with at least 12 months of follow-up. Thirty-four (91.9%) of 37 children were seizure-free (class 1a) after a median follow-up time of 3.7 years (range 12 month to 14.8 years). SIGNIFICANCE: We confirm the efficacy and safety of vertical parasagittal hemispherotomy as described by Delalande in a consecutive series of patients treated at our center since 1998. In addition, complete disconnection of the hemisphere in patients with MCD and/or patients with significant involvement of the insula was possible without the complications usually reported with other techniques.

Disconnective surgery in posterior quadrantic epilepsy: experience in a consecutive series of 10 patients.

OBJECT: Outcomes following functional hemispherotomy in patients with drug-resistant epilepsy have been well described. However, studies reporting long-term longitudinal outcomes after subhemispheric disconnective epilepsy surgery are still limited. METHODS: The authors conducted a retrospective review of prospectively collected data of 10 children who underwent temporoparietooccipital (TPO) disconnective surgery at the Vienna Pediatric Epilepsy Center. RESULTS: There were 3 males and 7 females (median age 8.7 years; range 4.2-22.1 years). The affected hemisphere was the left in 3 patients and the right in 7. The patients' median age at seizure onset was 3.0 years (range 0.2-8.3 years). The median duration of epilepsy before surgery was 5.2 years (range 1.3-17.2 years). The underlying pathology was TPO malformation of cortical development in 5 patients, and venous infarction, posterior hemispheric quadrant atrophy, Sturge-Weber syndrome, cortical involvement of a systemic lupus erythematosus, and gliosis after cerebral tumor treatment in 1 each. In 6 children, a pure TPO disconnection was performed; in 2 patients, the temporal lobe was resected and parietooccipital disconnection was performed. The 2 remaining patients had had previous epilepsy surgery that was extended to a TPO disconnection: disconnection of the occipital lobe (n = 1) and resection of the temporal lobe (n = 1). The authors encountered no complications while performing surgery. No patient needed blood replacement therapy. No patient developed CSF disturbances that warranted treatment. Nine of 10 patients are currently seizure free since surgery (Wieser Class 1a) at a median follow-up time of 2.1 years (range 4 months to 8.1 years). CONCLUSIONS: Temporoparietooccipital disconnection is a safe and effective motor-sparing epilepsy surgery in selected cases. Technical adjuncts facilitate a better intraoperative visualization and orientation, thereby enabling a less invasive approach than previously suggested.

Focal signs in infantile spasms.

BACKGROUND: Infantile spasms belong to the group of epileptic encephalopathies that typically occur in early infancy and are often associated with severe developmental delay. Little is known about whether focal features are part of the syndrome and thus occur independently of etiology, or whether focal features always indicate a cerebral lesion. METHODS: In our study we included all patients with infantile spasms documented by prolonged video-electroencephalogram (EEG) monitoring between 7/2003 and 11/2020 and analysed symptoms such as tonic posturing, clonic movements, deviation of the eyes and unilateral deviation of the mouth. These symptoms were classified as lateralizing or non-lateralizing and the correlation to the presence of a lesion was investigated. RESULTS: Eighteen patients (9 w/9 m) were included in the study. Lateralizing tonic posturing was found in 66.6% of the patients. Deviation of the eyes to one side and unilateral deviation of the mouth were detected in 61.1% and 11.1% of patients, respectively. Taking into account all symptoms (tonic posturing, clonic movements, deviation of the eyes, unilateral deviation of the mouth), focal signs were observed in a total of 94.4%, with only half of the total patient population having a cerebral lesion. CONCLUSION: In our study, lateralizing symptoms in infantile spasms occurred independently of the presence of a lesion. In contrast, focal symptoms in older children or adults usually correlate with the presence and localization of a lesion. A possible hypothesis could be that the brain is still maturing in infancy.

The Ketogenic Diet Including Breast Milk for Treatment of Infants with Severe Childhood Epilepsy: Feasibility, Safety, and Effectiveness.

Objective: The ketogenic diet (KD) is a high-fat and restricted carbohydrate diet for treating severe childhood epilepsy. In infants, breast milk is usually fully replaced by a ketogenic formula. At our center, mothers are encouraged to include breastfeeding into the KD if still breastfeeding. This retrospective study describes achievement and maintenance of ketosis with or without inclusion of breast milk. Methods: Data were retrieved from a prospective longitudinal database of children treated with KD for epilepsy analyzing infants <1 year of age. The time to achieve clinically relevant ketosis (≥2 mmol/L beta-hydroxybutyrate) was compared with and without inclusion of breast milk into standard KD. Ketosis, nutritional intakes, effectiveness, adverse effects, and successful continuation of breastfeeding were evaluated. Results: A total of 79 infants were eligible for analysis. In 20% (16), breast milk was included. Infants with breast milk included into the KD achieved relevant ketosis in 47 hours (interquartile range [IQR] 24-95) compared with 41 hours (IQR 22-70; p = 0.779) in infants with standard KD. Beta-hydroxybutyrate at day 2 was 3.1 mmol/L (IQR 0.5-4.9) and 3.8 mmol/L (IQR 2.2-4.9). Infants with breast milk included received higher amounts of carbohydrates at baseline and calories at 3 months. Seizure freedom and adverse effects showed no relevant differences. No infections occurred in infants receiving breast milk. In two infants, KD was initiated with breast-feds after bottle-feeding KD formula. In 31%, breastfeeding was continued after the KD, and in 25%, inclusion of breast milk and breastfeeding was maintained until complete weaning. Before discharge from hospital, the amount of breast milk included was median 90 mL/day (IQR 53-203) equivalent to median 9% (IQR 6-15). Conclusions: Appropriate ketosis was achieved in most infants and maintained within 48 hours. Incorporation of breast milk into KD is feasible, safe, and effective.

Effects of the ketogenic diet on platelet counts and global coagulation tests in childhood epilepsy.

PURPOSE: Several antiseizure drugs (ASD), especially Valproic acid (VPA), influence platelet counts and coagulation parameters. The ketogenic diet (KD), established in drug-resistant epilepsy, is combined with ASDs. Bruising and prolonged bleeding times during KD have been described, but whether hemostatic changes result from the KD or from concomitant ASDs, remains unclear. Aim of the present study was to evaluate bleeding, platelet counts and global coagulation tests prior to and during KD in childhood epilepsy. METHOD: Consecutive children treated with KD were systematically observed for bleeding. Serial measurements of platelet counts and global coagulation tests (APTT, PT and fibrinogen) were obtained at baseline and during KD (at 1, 3, 6 and 12 months). Children with KD monotherapy, concomitant VPA, or other ASDs were compared. RESULTS: Among 162 children receiving KD, we observed neither bleeding in daily life nor perioperative bleeding in those undergoing surgery (n = 25). Most children had normal platelet counts and coagulation parameters. Only a few had transient mild thrombocytopenia and mildly prolonged APTT values, not indicative of a bleeding risk. Even KD combined with VPA did not cause relevant coagulopathy. Unexpectedly, we found mild thrombocytosis in 24 % of patients prior to KD, which was most pronounced in yet untreated epilepsy. Thrombocytosis steadily resolved during KD. CONCLUSIONS: During KD treatment of childhood epilepsy, we observed neither bleeding symptoms nor laboratory results indicating a bleeding risk. Unexpectedly, mild thrombocytosis was present in 24 % at baseline, normalising during KD. Thrombocytosis may reflect the underlying inflammatory process of untreated epilepsy and requires further study.

Focal lesions in the splenium of the corpus callosum in patients with epilepsy.

PURPOSE: A focal lesion in the splenium of the corpus callosum is a rare finding in patients with epilepsy. Intoxication with antiepileptic drugs, edema after generalized seizures, or a rapid change of antiepileptic drug levels have been proposed as possible mechanisms. The aim of the present study was to analyze the relationship between this lesion and possible etiologic factors. PATIENTS AND METHODS: We analyzed the magnetic resonance imaging (MRI) scans of 1,050 patients undergoing prolonged video-EEG (electroencephalography) monitoring and identified 24 patients with a focal lesion in the splenium of the corpus callosum. Twenty-four age- and gender-matched temporal lobe epilepsy patients without such a lesion served as a control group. We evaluated the following parameters for their possible etiologic significance: epilepsy syndrome, seizure types in medical history, seizure frequency during the past year prior to admission for prolonged video-EEG monitoring, localization of interictal spikes and ictal EEG patterns in patients with focal epilepsies as documented during prolonged video-EEG-monitoring, seizure types and seizure frequency during prolonged video-EEG monitoring, past as well as current antiepileptic medication, withdrawal of antiepileptic drugs during monitoring including duration of medication withdrawal, and finally drug levels above the therapeutic range. RESULTS: The parameters analyzed showed no significant difference between the group of patients with focal lesions in the splenium of the corpus callosum and the control group. CONCLUSION: We could not identify a single etiologic factor responsible for the lesion in the splenium of the corpus callosum.

Single stage epilepsy surgery in children and adolescents with focal cortical dysplasia type II - Prognostic value of the intraoperative electrocorticogram.

OBJECTIVE: To evaluate prospectively the informative/prognostic value of epileptic discharges in the post-resection ECoGs of children with drug-resistant epilepsies and Focal Cortical Dysplasia type II (FCD-II). METHODS: Included were consecutive patients with focal epilepsies and suspected FCD-II who were planned for single-stage epilepsy surgery based on non-invasive presurgical evaluation results. Intraoperative ECoGs were recorded using a 32-channel system with strip- and/or grid-electrodes. Spikes were defined as transients with a mainly negative component and duration of 20-70 ms. Fast activity was defined as rhythmic bursts of polyspikes >13 Hz. All ECoGs were analysed visually. The significance of both spikes and fast activity in the post-resection ECoG for seizure outcomes 24 months after surgery was evaluated. RESULTS: Data from 18 patients (five girls) were analysed. 10/18 patients (55.6%) showed spikes in their post-resection ECoGs, five of them showed additional fast activity. 24 months after surgery, 12/18 patients (66.7%) were seizure-free. There was a significant correlation between unfavorable seizure outcomes and fast activity in the post-resection ECoGs (p = 0.009), whereas spikes alone were not predictive (p = 0.502). CONCLUSION: Even when recorded with non-sophisticated techniques, presence of fast activity in post-resection ECoGs might be a valid negative outcome-predictor after surgery in paediatric patients with FCD-II associated drug-resistant epilepsies. SIGNIFICANCE: Fast activity recorded with a relatively simple ECoG equipment seems also to have prognostic significance and by this might be an alternative to HFOs recorded with highly sophisticated and expensive technologies.

Epilepsy surgery in infants : Safety issues and developmental outcome.

PURPOSE: To evaluate the efficacy and safety of epilepsy surgery in infants. METHODS: Included were patients with epilepsy onset during the first year of life, epilepsy surgery before the age of 36 months at the study center and a minimum follow-up of 24 months after surgery. Patients who were surgically treated before the age of 12 months were compared with those between 13 and 36 months. Group differences with respect to efficacy (seizure outcomes and developmental progress measured by the social interaction quotient, SIQ) as well as safety (i. e. peri-operative complication rates) were analyzed. RESULTS: A total of 20 patients (10 girls) were included: 10 (five girls) were operated on as infants (median age at surgery 9.0 months, median disease duration prior to surgery 5.0 months) and 10 (5 girls) were operated on as toddlers (median age at surgery 24.0 months, median disease duration prior to surgery 18.0 months). Favorable seizure outcomes (Wieser 1a and 1) were seen in 80% (8/10) of the infants and 60.0% (6/10) of toddlers. Developmental progress was most evident in infants who were seizure-free and off medication (median SIQ 85.5 versus 63.0 in the toddler group). There were no differences between the two groups with respect to safety aspects. CONCLUSION: Despite several limitations due to the small number of patients included, our results are in favor of early epilepsy surgery in infants with drug-resistant epilepsy.

Ketogenic parenteral nutrition in 17 pediatric patients with epilepsy.

Objective: 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. Methods: Children with epilepsy receiving kPN were included. A computer-based algorithm was established on the basis of guidelines of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN): fat intake not exceeding 4 g/kg/day, age-adequate supply of protein, electrolytes, vitamins, and trace elements, but reduced carbohydrates. Primary outcome was successfully reaching relevant ketosis, defined as beta-hydroxybutyrate plasma level of ≥ 2 mmol/L. Efficacy was defined as seizure reduction ≥50% in de novo kPN and maintenance of response in children already on a ketogenic diet (KD). Safety was assessed by adverse effects, laboratory findings, and the appropriateness of nutritional intake. Results: Seventeen children (median 1.84 years) were studied, of which 76% (13/17) were already on an oral ketogenic diet. Indications for kPN were surgery, status epilepticus, vomiting, food refusal, and introduction of enteral feeding in neonates. The parenteral fat/nonfat ratio was mean 0.9 (±0.3; range 0.6-1.5). Relevant ketosis was reached in 10 children (median 2.9 mmol/L), but not in 7 (median = 1.4 mmol/L). In de novo kPN, significant response was observed in 50% (2/4); in patients previously responding to the KD (77%, 10/13), response was maintained. A significant correlation between the degree of ketosis and seizure reduction (correlation coefficient = 0.691; p = .002) was observed. Only mild and transient adverse events occurred during kPN. Significance: KPN with fat intake of 3.5-4.0 g/kg/day was safe and effective. KPN was tailored according to guidelines and individual nutritional needs. In nearly half of the patients, ketosis was lower than during oral KD. Despite this, seizures remained controlled.

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.