Objective
Dravet syndrome (DS) is a drug‐resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, ...fenfluramine (FFA) proved to be safe and effective in DS.
Methods
DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add‐on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months.
Results
Fifty‐two patients were enrolled, with a median age of 8.6 years (interquartile range IQR = 4.1‐13.9). Forty‐five (86.5%) patients completed the efficacy analysis. The median follow‐up was 9.0 months (IQR = 3.2‐9.5). At last follow‐up visit, there was a 77.4% median reduction in convulsive seizures. Thirty‐two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure‐free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA.
Significance
In this real‐world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.
Dravet syndrome (DS) is a rare and severe form of genetic epilepsy characterized by cognitive and behavioural impairments and progressive gait deterioration. The characterization of gait parameters ...in DS needs efficient, non-invasive quantification. The aim of the present study is to apply nonlinear indexes calculated from inertial measurements to describe the dynamics of DS gait. Twenty participants (7 M, age 9-33 years) diagnosed with DS were enrolled. Three wearable inertial measurement units (OPAL, Apdm, Portland, OR, USA; Miniwave, Cometa s.r.l., Italy) were attached to the lower back and ankles and 3D acceleration and angular velocity were acquired while participants walked back and forth along a straight path. Segmental kinematics were acquired by means of stereophotogrammetry (SMART, BTS). Community functioning data were collected using the functional independence measure (FIM). Mean velocity and step width were calculated from stereophotogrammetric data; fundamental frequency, harmonic ratio, recurrence quantification analysis, and multiscale entropy (τ = 1...6) indexes along anteroposterior (AP), mediolateral (ML), and vertical (V) axes were calculated from trunk acceleration. Results were compared to a reference age-matched control group (112 subjects, 6-25 years old). All nonlinear indexes show a disruption of the cyclic pattern of the centre of mass in the sagittal plane, quantitatively supporting the clinical observation of ataxic gait. Indexes in the ML direction were less altered, suggesting the efficacy of the compensatory strategy (widening the base of support). Nonlinear indexes correlated significantly with functional scores (i.e., FIM and speed), confirming their effectiveness in capturing clinically meaningful biomarkers of gait.
Targeting pro-inflammatory events to reduce seizures is gaining momentum. Experimentally, antagonism of inflammatory processes and of blood-brain barrier (BBB) damage has been demonstrated to be ...beneficial in reducing status epilepticus (SE). Clinically, a role of inflammation in the pathophysiology of drug resistant epilepsies is suspected. However, the use anti-inflammatory drug such as glucocorticosteroids (GCs) is limited to selected pediatric epileptic syndromes and spasms. Lack of animal data may be one of the reasons for the limited use of GCs in epilepsy. We evaluated the effect of the CG dexamethasone in reducing the onset and the severity of pilocarpine SE in rats. We assessed BBB integrity by measuring serum S100β and Evans Blue brain extravasation. Electrophysiological monitoring and hematologic measurements (WBCs and IL-1β) were performed. We reviewed the effect of add on dexamethasone treatment on a population of pediatric patients affected by drug resistant epilepsy. We excluded subjects affected by West, Landau-Kleffner or Lennox-Gastaut syndromes and Rasmussen encephalitis, known to respond to GCs or adrenocorticotropic hormone (ACTH). The effect of two additional GCs, methylprednisolone and hydrocortisone, was also reviewed in this population. When dexamethasone treatment preceded exposure to the convulsive agent pilocarpine, the number of rats developing status epilepticus (SE) was reduced. When SE developed, the time-to-onset was significantly delayed compared to pilocarpine alone and mortality associated with pilocarpine-SE was abolished. Dexamethasone significantly protected the BBB from damage. The clinical study included pediatric drug resistant epileptic subjects receiving add on GC treatments. Decreased seizure frequency (≥ 50%) or interruption of status epilepticus was observed in the majority of the subjects, regardless of the underlying pathology. Our experimental results point to a seizure-reducing effect of dexamethasone. The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures.
Summary
Objective
PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and ...autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors.
Methods
We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency.
Results
At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124).
Significance
We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.
The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in ...human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C > G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
•We have identified a new heterozygous de novo mutation of HCN1 (p.L157V) in a patient with genetic generalized epilepsy (GGE).•The L157V mutation reduces the HCN1 current in both CHO cell and neonatal neurons, in a dominant manner.•When expressed in neurons, mutant channels reduce the firing threshold and increase excitability.•This is the first evidence that loss-of-function HCN1 mutations can predispose to GGE.
Aim
To identify factors that may predict and affect the risk of relapse in anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis.
Method
This was a retrospective study of an Italian cohort of ...patients with paediatric (≤18y) onset anti‐NMDAR encephalitis.
Results
Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo–18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2–4). Time to first relapse was median 31.5 months (range 7–89mo). Severity at first relapse was lower than onset (median modified Rankin Scale mRS 3, range 2–4, vs median mRS 5, range 3–5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046–0.941; p=0.042). Neurological outcome at follow‐up did not differ significantly between patients with relapsing and monophasic disease (mRS 0–1 in 39/49 vs 12/13; p=0.431), although follow‐up duration was significantly longer in relapsing (median 84mo, range 14–137mo) than in monophasic patients (median 32mo, range 4–108mo; p=0.002).
Interpretation
Relapses may occur in about one‐fifth of children with anti‐NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow‐up. Aggressive immune therapy at onset may reduce risk of relapse.
What this paper adds
Relapses of anti‐N‐methyl‐D‐aspartate receptor encephalitis may span over a long period.
Relapses were not associated with severity in the acute phase or outcome at follow‐up.
Aggressive immune therapy at onset appears to decrease risk of relapse.
What this paper adds
Relapses of anti‐N‐methyl‐D‐aspartate receptor encephalitis may span over a long period.
Relapses were not associated with severity in the acute phase or outcome at follow‐up.
Aggressive immune therapy at onset appears to decrease risk of relapse.
Summary
Purpose: To clarify the role of epilepsy and genetic background in determining the cognitive outcome of patients with Dravet syndrome.
Methods: In this retrospective study, we reviewed the ...clinical history and cognitive development of 26 patients who had been followed with standardized evaluations since seizure onset. The cognitive outcome was quantified as differential general quotient (dGQ) between ages 12 and 60 months. Statistical analysis correlated the dGQ with genotype and epilepsy course.
Key Findings: Epilepsy started at the mean age of 5.6 months. All patients experienced prolonged convulsive seizures, whereas absences and myoclonus were reported in 17. Cognitive outcome was poor in almost all patients; the mean dGQ was 33 points, varying from 6–77 points. The analysis of individual cognitive profiles identified seven patients in whom the dGQ was <20 points; the main clinical characteristic in this subset of patients was lack of early absences and myoclonus. The statistical analysis of the whole series failed to reveal significant differences in cognitive outcome with regard to the presence of SCN1A mutations and their type. In particular, mutation‐carrier patients with the best cognitive outcome harbored either missense or truncating mutations.
Significance: Dravet syndrome encompasses different epileptic and cognitive phenotypes that probably result from both genetic and epigenetic factors. In this series, early appearance of myoclonus and absences was associated with the worst cognitive outcome.
A stepwise increase in the utilization of ketogenic dietary therapies for drug-resistant epilepsy has been observed in Italy in the last decade, although it is still considered often underused in ...many centers when compared to other countries. The Dietary Therapy Study Group of the Italian League against Epilepsy proposes practical recommendations to improve shared knowledge and facilitate the application of ketogenic dietary therapies, optimizing its efficacy and tolerability. The experts involved (11 child neuropsychiatrists, two adult neurologists, one psychologist, one pharmacologist, one pediatric endocrinologist, one representative of patients' associations, and three dietitians and clinical nutritionists) responded to a survey on current clinical practice issues and were asked to discuss controversial topics related to supplementation, long-term maintenance, transition, and a multidisciplinary approach to ketogenic dietary therapies. Practical indications for patient selection, diet initiation, management, side effects prevention, and follow-up are provided.
•Forty-nine patients with progressive myoclonus epilepsy took perampanel in add-on.•Perampanel reduced myoclonus severity as assessed by minimal myoclonus scale.•Action myoclonus improved greatly as ...measured by the unified myoclonus rating scale.•Convulsive seizures were reduced by >50%.•Side effects occurred in 44.8% patients, the most common being irritability.
Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales.
Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2–12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4–6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy.
Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the ‘Action myoclonus’ section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness.
PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.
Variants in
are associated with a wide spectrum of epileptic phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), non-EIMFS developmental and epileptic encephalopathies, ...autosomal dominant or sporadic sleep-related hypermotor epilepsy, and focal epilepsy. Here, we describe a girl affected by drug-resistant focal seizures, developmental delay and behavior disorders, caused by a novel,
heterozygous missense
variant (c.2809A > G, p.S937G). Functional characterization in transiently transfected Chinese Hamster Ovary (CHO) cells revealed a strong gain-of-function effect determined by the
p.S937G variant compared to wild-type, consisting in an increased maximal current density and a hyperpolarizing shift in current activation threshold. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant
channels. Treatment of the proband with fluoxetine led to a prolonged electroclinical amelioration, with disappearance of seizures and better EEG background organization, together with an improvement in behavior and mood. Altogether, these results suggest that, based on the proband's genetic and functional characteristics, the antidepressant drug fluoxetine may be repurposed for the treatment of focal epilepsy caused by gain-of-function variants in
. Further studies are needed to verify whether this approach could be also applied to other phenotypes of the
-related epilepsies spectrum.
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