The pharmacologic treatment of Dravet syndrome Chiron, Catherine; Dulac, Olivier
Epilepsia (Copenhagen),
April 2011, 2011-Apr, 2011-04-00, 20110401, Volume:
52, Issue:
s2
Journal Article
Peer reviewed
Summary
Dravet syndrome (DS) is one of the most pharmacoresistant epilepsy syndromes. Valproate is used as a first‐line agent to prevent the recurrence of febrile seizures and oral/nasal/rectal ...benzodiazepine is used for any long‐lasting seizures, but these agents are most often insufficient. Lamotrigine, carbamazepine, and high doses of intravenous phenobarbital should be avoided because they may worsen seizures. Topiramate, levetiracetam, bromide, and the ketogenic diet may provide substantial efficacy as adjunctive therapy/procedure. Stiripentol is the only compound that proved its efficacy in DS through two independent randomized placebo‐controlled trials, when combined with valproate and clobazam. Their dose has to be decreased to minimize the side effects (mostly loss of appetite) resulting from pharmacokinetic interactions of stiripentol powerfully inhibiting cytochromes P450. Stiripentol acts as a γ‐aminobutyric acid (GABA)ergic agent, mainly via the α3 subunit of GABAA receptors. Stiripentol (Diacomit) was approved as an orphan drug in 2007 in Europe for adjunctive therapy in DS. Up to now, >500 children have been safely treated, and recent experiment in Japan confirmed stiripentol benefit in DS children with comedications other than valproate and clobazam. Because early status epilepticus is likely to negatively impact cognitive outcome, we recommend the introduction of stiripentol as soon as the diagnosis of DS is clinically confirmed. Topiramate and the ketogenic diet are alternatives in pharmacoresistant cases.
Summary Fever-induced refractory epileptic encephalopathy in school-aged children (FIRES), and idiopathic hemiconvulsion–hemiplegia syndrome (IHHS) are both triggered by fever, although evidence for ...a causal microorganism or an autoimmune phenomenon is lacking. FIRES begins in school age with status epilepticus lasting several weeks, involves perisylvian areas including mesial temporal structures, and is followed by pharmacoresistant epilepsy with major cognitive deterioration. IHHS begins in infancy with unilateral clonic status epilepticus and is followed by hemiplegia with pharmacoresistant epilepsy. The aetiology of FIRES and IHHS remains unknown, although clinical features and experimental models point to a likely vicious cycle involving inflammation and seizure activity that depends on the stage of brain maturation. We therefore propose to group these conditions under the concept of acute encephalopathy with inflammation-mediated status epilepticus. In addition to preliminary but encouraging clinical observations, there are theoretical reasons to consider the ketogenic diet as an early means to control both seizures and inflammation.
Summary
Purpose: Fever induced refractory epileptic encephalopathy in school age children (FIRES) is a devastating condition initiated by prolonged perisylvian refractory status epilepticus (SE) ...triggered by fever of unknown cause. SE may last more than 1 month, and this condition may evolve into pharmacoresistant epilepsy associated with severe cognitive impairment. We aimed to report the effect of ketogenic diet (KD) in this condition.
Methods: Over the last 12 years we collected data of nine patients with FIRES who received a 4:1 ratio of fat to combined protein and carbohydrate KD. They presented with SE refractory to conventional antiepileptic treatment.
Results: In seven patients, KD was efficacious within 2–4 days (mean 2 days) following the onset of ketonuria and 4–6 days (mean 4.8 days) following the onset of the diet. In one responder, early disruption of the diet was followed by relapse of intractable SE, and the patient died. Epilepsy affected the other six responders within a few months.
Discussion: KD may be an alternative therapy for refractory SE in FIRES and might be proposed in other types of refractory SE in childhood.
Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing ...in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition.
Epileptic encephalopathies are conditions in which neurologic deterioration results mainly from epileptic activity. It can be due to very frequent or severe seizures, or to subcontinuous paroxysmal ...interictal activity. The former consists mainly of severe myoclonic epilepsy in infancy (SMEN), in which patients exhibit seizures from the middle of the first year of life with repeated episodes of status epilepticus, and migrating partial epilepsy in infancy, in which, from the first trimester of life, partial seizures affect various areas of the cortex randomly and in a subcontinuous fashion. Cases with subcontinuous paroxysmal interictal activity affect newborns with suppression bursts, thus consisting of either Ohtahara syndrome or neonatal myoclonic encephalopathy, and infants with infantile spasms (IS), although rare cases do not start until age 4 years. In childhood, it consists of various types of generalized seizures combined with either slow spike–waves of the Lennox–Gastaut syndrome (LGS) or with myoclonus and 3‐Hz spike–waves of myoclonic–astatic epilepsy, and continuous spike–waves in slow sleep (CSWS) combined with various neuropsychological patterns including Landau–Kleffner syndrome, frontal lobe syndrome, orofacial dyspraxia, or negative myoclonus. Management differs for all these syndromes, with the combination of clobazam (CLB) and stiripentol (STP) being promising for SMEN, vigabatrin (VGB) for IS, lamotrigine (LTG) for LGS, and steroids for CSWS. It is important to avoid potential drug‐induced worsening by phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), tiagabine (TGB), and VGB; in children and especially in infants, treatment with valproate is preferred each time the proper diagnosis is not reached.
Phenobarbital produces its anti-epileptic actions by increasing the inhibitory drive of γ-aminobutyric acid. However, following recurrent seizures, γ-aminobutyric acid excites neurons because of a ...persistent increase of chloride raising the important issue of whether phenobarbital could aggravate persistent seizures. Here we compared the actions of phenobarbital on initial and established ictal-like events in an in vitro model of mirror focus. Using the in vitro three-compartment chamber preparation with the two hippocampi and their commissural fibres placed in three different chambers, kainate was applied to one hippocampus and phenobarbital contralaterally, either after one ictal-like event or after many recurrent ictal-like events that produce an epileptogenic mirror focus. Field, perforated patch and single-channel recordings were used to determine the effects of γ-aminobutyric acid and their modulation by phenobarbital, and alterations of the chloride cotransporters were investigated using sodium-potassium-chloride cotransporter 1 and potassium chloride cotransporter 2 antagonists, potassium chloride cotransporter 2 immunocytochemistry and sodium-potassium-chloride cotransporter 1 knockouts. Phenobarbital reduced initial ictal-like events and prevented the formation of a mirror focus when applied from the start. In contrast, phenobarbital aggravated epileptiform activities when applied after many ictal-like events by enhancing the excitatory actions of γ-aminobutyric acid due to increased chloride. The accumulation of chloride and the excitatory actions of γ-aminobutyric acid in mirror foci neurons are mediated by the sodium-potassium-chloride cotransporter 1 chloride importer and by downregulation and internalization of the chloride-exporter potassium-chloride cotransporter 2. Finally, concomitant applications of the sodium-potassium-chloride cotransporter 1 antagonist bumetanide and phenobarbital decreased excitatory actions of γ-aminobutyric acid and prevented its paradoxical actions on mirror focus. Therefore, the history of seizures prior to phenobarbital applications determines its effects and rapid treatment of severe potentially epileptogenic-neonatal seizures is recommended to prevent secondary epileptogenesis associated with potassium chloride cotransporter 2 downregulation and acquisition of the excitatory γ-aminobutyric acid phenotype.
Ketogenic diet (KD) is an emerging treatment option for super-refractory status epilepticus (SRSE). We evaluated the effectiveness of KD in patients presenting SRSE including NORSE (and its ...subcategory FIRES).
A retrospective review of the medical records was performed at the Necker Enfants Malades Hospital. All children with SRSE in whom KD was started during the last 10 years were included. A systematic search was carried out for all study designs, including at least one patient of any age with SRSE in whom KD was started. The primary outcome was the responder rate and Kaplan-Meier survival curves were generated for the time-to-KD response. As secondary outcomes, Cox proportional hazard models were created to assess the impact of NORSE-related factors on KD efficacy.
Sixteen children received KD for treatment of SRSE, and three had NORSE presentation (one infectious etiology, two FIRES). In medical literature, 1,613 records were initially identified, and 75 were selected for review. We selected 276 patients receiving KD during SRSE. The most common etiology of SRSE was acute symptomatic (21.3%), among these patients, 67.7% presented with NORSE of immune and infectious etiologies. Other etiologies were remote symptomatic (6.8%), progressive symptomatic (6.1%), and SE in defined electroclinical syndromes (14.8%), including two patients with genetic etiology and NORSE presentation. The etiology was unknown in 50.7% of the patients presenting with cryptogenic NORSE, of which 102 presented with FIRES. Overall, most patients with NORSE benefit from KD (
< 0.004), but they needed a longer time to achieve RSE resolution after starting KD compared with other non-NORSE SRSE (
= 0.001). The response to KD in the NORSE group with identified etiology compared to the cryptogenic NORSE was significantly higher (
= 0.01), and the time to achieve SE resolution after starting KD was shorter (
= 0.04).
The search for underlying etiology should help to a better-targeted therapy. KD can have good efficacy in NORSE; however, the time to achieve SE resolution seems to be longer in cryptogenic cases. These findings highlight the therapeutic role of KD in NORSE, even though this favorable response needs to be better confirmed in prospective controlled studies.
Highlights • Pathophysiology explains not only epilepsy phenotype of Dravet syndrome but also non-epileptic features, and this condition should therefore be considered a disease. • Other genes than ...SCN1A produce the Dravet syndrome phenotypes but clinical reports do not provide data regarding non epileptic features. • The therapeutic strategy for Dravet syndrome should be modified, questioning chronic use of benzodiazepines. • To improve full-blown phenotype of Dravet disease requires targeting NaV 1.1 channels modulation, including SCN1A gene therapy.
Eight patients, seven girls and one boy, had CDKL5 gene mutation, duplication, or deletion. Epileptic spasms started at a mean age of 3.5 months (range = 4 weeks–8 months). In five cases, tonic ...seizures preceded spasms at a median age of 6 weeks. In one patient who started at 8 months, spasms had a component of terror on awakening, reminding sleep terror. In two patients, electroencephalogram polygraphy of a so-called tonic seizure revealed that the tonic phase was followed by an overlooked clonic phase and then by a cluster of spasms during which each spasm was preceded by a brief clonic jerk revealed by electromyography. This sequence is rather particular and can be an early diagnostic clue. Progressive transition from this seizure type to epileptic spasms in clusters seems to result from increasing expression of the CDKL5 gene, as the child grows older. Five patients responded to the combination of vigabatrin and zonisamide.
•peculiar ictal sequence is identifiable on (video-EEG/polygraphy) and could be an early diagnostic clue•clusters of spasms are very early sign of encephalopathy appearing initially in the structure of this peculiar type of seizures.•the combination of vigabatrin and zonisamide is promising and should be given as soon as CDKL5 mutation is suspected
Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy ...patients and only a small minority of HSV-1-infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-α/β and -λ antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.
PDF
