Diagnosis, epilepsy treatment and supports for neurodevelopment in children with Dravet Syndrome: Caregiver reported experiences and needs.

BACKGROUND: Dravet syndrome is a rare infantile onset epilepsy syndrome encompassing treatment resistant epilepsy and neurodevelopmental difficulties. There is limited data regarding caregiver experiences of diagnosis, treatment and supports for the associated neurodevelopmental problems. METHOD: Semi-structured interviews were conducted with caregivers of 36/48 children (75% of total population in Sweden) with Dravet syndrome. Data was analysed using thematic analysis. RESULTS: Regarding the diagnostic experience, themes were: Delays in diagnostic process, genetic testing not optimal, communication of Dravet syndrome diagnosis and support and information soon after diagnosis. Caregivers felt that delays in diagnosis and testing could have been avoided whilst experiences of communication of diagnosis and support after diagnosis varied. In terms of treatment for seizures, the themes were: Satisfied with treatment, emergency treatment, treatment with antiseizure medications, strategies to control seizures via temperature regulation/avoidance of infections and use of equipment and aids. Caregivers were in the main accepting that seizures in Dravet syndrome are very difficult to treat and that seizure freedom is often an unachievable goal. Many felt frustrated that they were expected to take responsibility with respect to choice of medication. They often employed strategies (e.g., avoidance of physical activity) to reduce seizures or their impact. In terms of supports for neurodevelopmental problems, the themes were: Struggled to access support, lack of integrated healthcare and satisfaction with school. Many caregivers felt that accessing necessary supports for their children and developmental and behavioural needs was a struggle and that the provision of support often lacked integration e.g., lack of collaboration between child's disability service and school. Caregivers also expressed a desire that there would be better knowledge of Dravet syndrome in emergency departments and schools, that care would be better integrated and that there would be more supports for assessment and interventions regarding the associated neurodevelopmental problems. CONCLUSION: The responses of caregivers of children with Dravet syndrome highlight the need for supports from diagnosis for both epilepsy and neurodevelopmental problems. Good examples of provision were identified but parents often felt they lacked support and support often came from providers who lacked knowledge of the syndrome. Collaboration between medical, disability and school services was often lacking.

Cannabis for the Treatment of Epilepsy: an Update.

PURPOSE OF REVIEW: For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy. RECENT FINDINGS: While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Cannabinoids in treatment-resistant epilepsy: A review.

Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled "Cannabinoids and Epilepsy".

Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures.

Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.

Dravet phenotype in a subject with a der(4)t(4;8)(p16.3;p23.3) without the involvement of the LETM1 gene.

We present a patient affected by Dravet syndrome. Thorough analysis of genes that might be involved in the pathogenesis of such phenotype with both conventional and next generation sequencing resulted negative, therefore she was investigated by a-GCH that showed the presence of an unbalanced translocation resulting in a der(4)t(4;8)(p16.3,p23.3). This was an unconventional translocation, different from the recurrent translocation affiliated with WHS and did not involve LETM1.

Reflex myoclonic epilepsy in infancy: a multicenter clinical study.

PURPOSE: To describe the clinical and electroencephalographic (EEG) features of reflex myoclonic epilepsy in infancy (RMEI) and long-term cognitive outcome. METHODS: We enrolled 31 children from 16 neuropediatric centres in Italy, who underwent clinical and video-EEG evaluation. Cognitive assessment was performed in all patients using standardized psychometric tests. RESULTS: The age at onset ranged from 3 to 24 months of age. Seizures were characterised in all patients by symmetric myoclonic seizures (MS), triggered by sudden unexpected acoustic (38.7%) or tactile stimuli (29%) or both (29%). Spontaneous attacks were reported in 32.2% of the cases. Ictal EEG showed generalized high-amplitude 3 Hz polyspike and wave discharges, synchronous with brief rhythmic bursts of electromyographic activity. Patients were re-evaluated after a period of 7.2 ± 5.6 years. The prognosis for seizure control was excellent in all cases and reflex MS disappeared spontaneously or after valproate treatment. The cognitive outcome was excellent in 90.3% of children. CONCLUSIONS: RMEI appears to be a variety of idiopathic generalized epilepsy with specific features that occurs in developmentally normal children.

Comprehensive care of children with Dravet syndrome.

The comprehensive care of a patient with Dravet syndrome encompasses both the "care" and the "cure" of the patient, and requires cooperation among family, doctors, and several other specialized caregivers to search for the attainment of the best quality of life for the patients and their families. Several issues peculiar to the disease to be faced while dealing with the patient are: (1) SMEI is an "evolving" disease that appears in an otherwise healthy child with symptoms that appear and mutate throughout the course of the disease; (2) the severity of the disease is not fully predictable at onset and appears to be individual-specific; (3) the seizures are invariably drug resistant and seizure freedom is not a realistic goal; and (4) in addition to seizures many other invalidating clinical problems, including cognitive impairment, behavior disorders, and a number of comorbidities characterize the disease course. The comprehensive caring must be physician-guided and patient-centered and implies a multidisciplinary approach to be built around the children and caregivers, who need to be guided through the steps of the diagnosis, treatments, and managements of the various comorbidities.

Electroencephalographic evaluation of gold wire implants inserted in acupuncture points in dogs with epileptic seizures.

The purpose of this study was to evaluate both, clinically and with electroencephalographic (EEG) recordings, the effect of gold wire implants in acupuncture points in dogs with uncontrolled idiopathic epileptic seizures. Fifteen dogs with such diagnosis were enrolled in the study. A first EEG recording was performed in all dogs under anaesthesia with xylazine (1mg/kg) and propofol (6 mg/kg) before the treatment protocol, and a second EEG was performed 15 weeks later. Relative frequency power, intrahemispheric coherence available through EEG, number of seizures and seizure severity were compared before and after treatment using a Wilcoxon signed-rank test. There were no significant statistical differences before and after treatment in relative power or in intrahemispheric coherence in the EEG recording. However, there was a significant mean difference in seizure frequency and seizure severity between control and treatment periods. After treatment, nine of the 15 dogs (60%) had at least a 50% reduction in seizures frequency during the 15 weeks established as follow-up of this treatment.

Serial MR imaging and 1H-MR spectroscopy in monozygotic twins with Tay-Sachs disease.

Four-year-old monozygotic female twins with early onset Tay-Sachs disease are described. The sisters showed similar slowly progressive clinical symptoms and deterioration, however the younger sister also demonstrated intractable myoclonus in the right leg. The serial MR images and (1)H-MR spectroscopy of the brain were obtained in both twins. MR images showed high intensity on T (2)-weighted image in the bilateral white matter, however there were no signal changes in the basal ganglia and thalamus during any of the phases. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was decreased in the both white matter lesions and the corpus striatum, and that of myoinositol (mI)/Cr was increased in the damaged white matter on MR spectroscopy. The elevation of the lactate peak was clearly demonstrated in the left basal ganglia of the younger sister; however it was not shown in cerebral lesions of the elder sister. Changes in metabolites on MR spectroscopy were closely linked to the respective clinical features of each twin. Follow-up examination by (1)H-MR spectroscopy is useful for the evaluation of neuronal changes in children with Tay-Sachs disease.

A magnetoencephalographic study of negative myoclonus in a patient with atypical benign partial epilepsy.

PURPOSE: To clarify the neurophysiological mechanism of epileptic negative myoclonus (NM) of a patient with atypical benign partial epilepsy whose NM was completely suppressed with ethosuximide. METHODS: Polygraphic recordings of whole-head type magnetoencephalography (MEG), EEG and electromyography were made during NM of the bilateral hands. The silent period of 200-400 ms duration in the bilateral biceps muscles was associated with paroxysmal spikes on EEG and MEG. Single equivalent current dipoles (ECD) were calculated for each spike component associated with NM and the estimated generator sources of spikes were superimposed on the patient's head MRI. RESULTS: The magnetic fields of each peak associated with NM showed clear single dipole pattern and ECDs of each peak were located in the neck and orofacial division of the primary motor cortex. CONCLUSIONS: Abnormal firing of the neck and orofacial division of the primary motor cortex was associated with NM generation. Taking the beneficial effect of ethosuximide (a T-type Ca2+ channel blocker in thalamic neurons and the corresponding cortex) and the MEG result together, it is suggested that abnormal interaction of the thalamo-cortical network might be closely related to the pathogenesis of NM.

Video-EEG study in an adult and a child with eyelid myoclonia with absences.

Two patients with eyelid myoclonia with absences (EMA) are described. Videotape of the eyelid myoclonia in one patient is presented. An interesting feature in one patient was the induction of clinical seizures only with daylight, and in another the presence of rare, focal, epileptiform discharges during drowsiness. Valproic acid only partially controlled eyelid myoclonia in both cases. Lamotrigine, alone or in combination with valproate, can be used as an alternative but was ineffective in our cases. [Published with video sequences].

Chess-playing epilepsy: a case report with video-EEG and back averaging.

A patient suffering from juvenile myoclonic epilepsy experienced myoclonic jerks, fairly regularly, while playing chess. The myoclonus appeared particularly when he had to plan his strategy, to choose between two solutions or while raising the arm to move a chess figure. Video-EEG-polygraphy was performed, with back averaging of the myoclonus registered during a chess match and during neuropsychological testing with Kohs cubes. The EEG spike wave complexes were localised in the fronto-central region. [Published with video sequences].

Reflex myoclonic epilepsy in infancy: a benign age-dependent idiopathic startle epilepsy.

Reflex myoclonic epilepsy of infancy is an idiopathic epileptic disorder characterized by myoclonic attacks, with onset in the first 2 years of life precipitated exclusively by unexpected tactile or auditory stimuli. We report on a 9 month-old infant with myoclonic attacks, which consisted of frequent clusters of up to 10 symmetric jerks affecting mainly the arms and the head occurring as reflex responses to unexpected auditory stimuli. There was no family history of epilepsy or febrile convulsions. Ictal EEG demonstrated a typical 3 Hz spike-wave pattern, while there were no abnormalities, either in wakefulness or during sleep. The neurodevelopmental examination was unremarkable and MRI of the brain was normal. The attacks disappeared 3 weeks after initiating sodium valproate, and have not reappeared since then (follow-up 3 years and 3 months); today, at 4 years of age, the patient has normal psycho-motor development. RMEI should be considered as an age-dependent, idiopathic, generalized epileptic syndrome with an apparently good prognosis[Published with video sequences].

Pyridoxine-dependent seizures responding to extremely low-dose pyridoxine.

We report on a male infant with pyridoxine dependency and seizures from birth, controlled with pharmacological doses of pyridoxine at 4 months of age. Seizures stopped between 30 and 80 days of age when very-low doses of pyridoxine were given in a multivitamin supplement. Daily dose was 0.5 mg that corresponded to 0.08 to 0.16 mg/kg/day when weight gain is considered. In previous reports doses have ranged from 0.2 to 30 mg/kg/day. Another distinctive feature was that this infant went into a coma and developed hypotonia and irregular breathing when pyridoxine was given by enteral tube which has usually been reported when the vitamin is given intravenously. Use of low doses of pyridoxine in multivitamin supplements could be a confounding factor for early diagnosis and appropriate treatment of pyridoxine-dependent seizures.

Early and late intracortical inhibition in juvenile myoclonic epilepsy.

PURPOSE: We investigated 15 patients with juvenile myoclonic epilepsy (JME) by subjecting them to single and paired transcranial magnetic stimulation to test the hypothesis that motor cortical inhibition may be abnormal in this form of benign epilepsy. METHODS: Different conditioning paradigms of paired transcranial magnetic stimulation were used with interstimulus intervals (ISIs) of varying lengths (1 to 400 milliseconds) to investigate changes in balance between excitatory and inhibitory intracortical circuits. RESULTS: Motor evoked potential (MEP) inhibition at ISIs of 1 to 4 milliseconds was significantly lower in JME patients than in age-matched healthy controls (p < 0.001), whereas no significant differences in MEP inhibition were noted at long ISIs (100 to 150 milliseconds). This pattern was observed in both hemispheres in seven of seven patients studied bilaterally and was present in both treated and untreated patients. There were no group differences between JME patients and controls in intracortical facilitation, motor threshold, MEP amplitude, and cortical silent period. CONCLUSIONS: We documented a different pattern of MEP inhibition in JME patients, suggesting impaired functioning of inhibitory interneuronal circuits, which may account for the hyperexcitability of the motor system in this form of epilepsy.

[Reflex benign myoclonic epilepsy of childhood. Apropos of a new case]. / Epilepsia mioclónica benigna refleja de la infancia. A propósito de una nueva observación.

INTRODUCTION: Recently a series of cases has been reported characterized by myoclonic crises similar to those occurring in benign myoclonic epilepsy of childhood. However, these crises only occurred after unexpected tactile or auditory stimuli. These clinical conditions represent a new epileptic syndrome, which is age-dependent and has been called benign myoclonic epilepsy of childhood. CLINICAL CASE: We present the case of a 12 month old girl with myoclonic crises which occurred only after auditory or tactile stimuli. The myoclonia could be set off whilst awake or asleep. No other types of crises or neurological changes were seen. A brother of the patient had had febrile convulsions. The EEG recorded during the crises showed generalized brief spike-and-wave discharges at 3 cycles/second. The intercritical EEG was normal whilst awake, but during sleep showed brief generalized discharges. After treatment with valproate was started the crises became less frequent. CONCLUSIONS: The case we describe is similar to those described by Ricci et al in 1995. We, therefore, consider it to fit the concept of reflex myoclonic epilepsy of childhood of benign character. We consider that this condition should be differentiated from other reflex epilepsies and epileptic syndromes with a predominance of myoclonia, including benign myoclonic epilepsy of childhood.

The controversy regarding diagnostic criteria for early myoclonic encephalopathy.

To re-evaluate the diagnostic criteria for early myoclonic encephalopathy (EME), the following study was done. During the past 2 years, five patients with erratic, fragmentary myoclonus of neonatal onset, in association with other types of seizures, were analyzed with regard to etiologies, electroclinical features and their evolution, using a series of examinations including electroencephalographies (EEGs) and metabolic investigations. Of these five patients, three were diagnosed to have non-ketotic hyperglycinemia (NKH); one was pyridoxine-dependent; the other was cryptogenic. Only two cases (one NKH and one cryptogenic) had initial typical suppression-burst (S-B) EEG pattern, which subsequently evolved into multiple paroxysmal abnormalities with random asynchronous attenuation (MP-AA) pattern. The other two cases with NKH had MP-AA EEG pattern throughout both awake and sleep recordings in two consecutive EEG studies. All three cases with NKH survived with increasing microcephaly, muscle tonicity; all developed infantile spasm with hypsarrhythmia on EEGs. The patient with pyridoxine-dependency had an initial MP-AA EEG pattern, which converted into S-B pattern after the first use of pyridoxine, eventually becoming normal after a supplement with the second-dose of pyridoxine. In conclusion, either S-B or MP-AA pattern may reflect the severity of the underlying pathologies or the disease stages. These results suggest that, from both etiological and electroclinical viewpoints, EME may represent a broader spectrum than previously recognized. The still ongoing controversy regarding whether the S-B pattern should be recognized as the sole EEG criteria for the diagnosis of EME needs further experience to clarify.

Opsoclonus-myoclonus associated with traditional medicine ingestion: case report.

A case of Opsoclonus-Myoclonus occurring in a young man, in association with traditional herbal medicine consumption is presented. Clinical and laboratory investigations did not reveal any of the known aetiological associations of the Opsoclonus-Myoclonus syndrome, raising the possibility that the traditional herbal medicine may be aetiologically implicated. This report highlights the need for proper identification and documentation of the contents of common herbal remedies and their possible side effects amongst Africans.

Reflex myoclonic epilepsy in infancy: a new age-dependent idiopathic epileptic syndrome related to startle reaction.

Benign myoclonic epilepsy of infancy (BMEI) is an idiopathic disorder characterized by spontaneous myoclonic attacks with onset in the first 2 years of life. We observed 6 neurologically normal infants (aged 6-21 months) with attacks that resembled those of BMEI but that occurred as reflex responses to unexpected auditory and tactile stimuli. four infants also had rare spontaneous attacks. These reflex attacks consisted of isolated muscle jerks or clusters of up to eight symmetric limb jerks affecting mainly the arms. Five of the children had a family history of epilepsy or febrile convulsions. Myoclonic attacks disappeared in 4-14 months. In 3 patients, the jerks stopped spontaneously; the others responded to valproate (VPA). Myoclonus could be elicited in wakefulness and in sleep. Ictal EEGs showed brief generalized spike- or polyspike-and-wave discharges. Interictal EEGs were normal during wakefulness; during sleep, brief generalized discharges were evident. We propose that reflex myoclonic epilepsy of infancy (RMEI) is a new age-dependent idiopathic generalized epileptic (IGE) syndrome, with an apparently good prognosis.