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.

Auditory processing following infantile spasms: An event-related potential study.

OBJECTIVES: To investigate acoustic auditory processing in patients with recent infantile spasms (IS). METHODS: Patients (n = 22; 12 female; median age 8 months; range 5-11 months) had normal preceding development, brain magnetic resonance imaging (MRI), and neurometabolic testing (West syndrome of unknown cause, uWS). Controls were healthy babies (n = 22; 11 female; median age 6 months; range 3-12 months). Event-related potentials (ERPs) and psychometry (Bayley Scales of Infant Development, Second Edition, BSID-II) took place at a month following IS remission. RESULTS: Following a repeated pure tone, uWS patients showed less suppression of the N100 at the mid-temporal electrodes (p = 0.006), and a prolonged response latency (p = 0.019). Their novelty P300 amplitude over the mid-temporal electrodes was halved (p = 0.001). The peak of the novelty P300 to environmental broadband sounds emerged later over the left temporal lobe in patients (p = 0.015), the lag correlating with duration of spasms (r = 0.547, p = 0.015). BSID-II scores were lower in patients (p < 0.001), with no correlation to ERP. SIGNIFICANCE: Complex acoustic information is processed poorly following IS. This would impair language. Treatment did not reverse this phenomenon, but may have limited its severity. The data are most consistent with altered connectivity of the cortical acoustic processing areas induced by IS.

[Clinical characteristics and prognosis analysis of vitamin B6 responsive infantile spasms].

OBJECTIVE: To analyze clinical characteristics, treatment and prognosis in a cohort of children with vitamin B6 responsive infantile spasms. METHOD: Ten patients were diagnosed as vitamin B6 responsive infantile spasms in Peking University First Hospital between January 2012 and May 2015.The clinical manifestations, diagnosis and treatment process, video-electroencephalogram, magnetic resonance imaging (MRI), epilepsy related genes and prognosis were retrospectively analyzed. RESULT: Of the 10 patients, 5 were male, and 5 were female. Eight of them were normal at birth, and the other 2 patients had intracranial hemorrhage or anoxia.The age of epilepsy onset was from 3.5 to 8.0 months.All patients presented spasms primarily.Interictal electroencephalogram (EEG) showed hypsarrhythmia at seizures onset. MRI showed normal in 8 patients, and subarachnoid hemorrhage or multiple encephalomalacia foci after hemorrhage respectively in the other 2 patients. The results of blood biochemical, cerebrospinal fluid examination and urinary metabolic screening were negative. Epilepsy related genes including ALDH7A1 gene analysis showed wild type in all patients. Two patients were classified as symptomatic and eight might be idiopathic or cryptogenic. The initial dose of vitamin B6 was 10.0 mg/(kg·d). The interval between seizures onset and taking vitamin B6 was 0 to 4.0 months. Seizures disappeared completely within a week after administration of vitamin B6 in 9 patients and in 1.5 months in one patient.Of the 8 patients whose seizures were controlled completely during the follow-up period, 7 patients' EEG recovered within 1.5 to 4.0 months and then continued to be normal. The EEG of the rest of a patient returned to normal, but showed abnormal discharges after stopping taking vitamin B6. Two patients' EEG continued abnormal and seizures recurred due to vitamin B6 withdrawal. At the last follow-up, seizures were controlled in all patients. Drug treatment in one case had stopped. Vitamin B6 was used in 9 patients at a dose of 0.4 to 10.0 mg/(kg·d). Among them, vitamin B6 monotherapy or coadministration with one low dose antiepileptic drug was applied in 6 or 3 patients respectively. The psychomotor development was normal in 5 patients, mild delay in 3 patients, and severe delay in 2 patients with autism behavior. Of the 2 symptomatic patients, one developed normally and the other showed severe delay. CONCLUSION: Vitamin B6 might have effects on both idiopathic or cryptogenic and symptomatic patients, especially for the former. High dose vitamin B6 should be first tried in all patients with infantile spasms. Patients who had response to vitamin B6 could be controlled within a short time and might have better outcomes. Seizures were not easy to relapse in those whose seizures were controlled and EEG recovered completely. Vitamin B6 could be gradually reduced during the course and might be withdrawn in the future. The recurrence of seizures was closely related to EEG abnormality.

Infraslow EEG changes in infantile spasms.

PURPOSE: Infantile spasms (IS) are a devastating epileptic encephalopathy syndrome of infancy. Analysis of infraslow EEG activity (ISA) has shown potential in the presurgical evaluation of patients with epilepsy and in differentiating between focal and generalized epilepsy syndromes. Infraslow EEG activity analysis may provide insights into the pathophysiology of some difficult-to-treat epilepsy syndromes, such as IS. To our knowledge, there are no published reports describing ISA in patients with IS. The purpose of this study was to describe ictal patterns of ISA in patients with IS and to correlate with clinical data. METHODS: EEG recordings of all cases of IS in the past 10 years at the Alberta Children's Hospital were reviewed. Inclusion criteria were a technically adequate video EEG recording that captured at least one spasm. For each patient, the first 10 confirmed spasms were examined. Spasms were evaluated for changes in ISA, which were either generalized, lateralized, or absent ISA (g-ISA, l-ISA, or n-ISA, respectively). Results were correlated with treatments, clinical course, and information pertinent to likely etiology of the IS. RESULTS: A total of 77% of spasms were associated with ISA; 57% with g-ISA, 20% l-ISA, and 21% n-ISA. All patients with exclusively g-ISA showed at least a partial response to initial therapy, while this was the case in 66.7% of those with at least some l-ISA and 50% of those with exclusively n-ISA. Other seizure types occurred in 60% of patients with exclusively g-ISA versus 83% with some l-ISA and all patients with exclusively n-ISA. CONCLUSIONS: Ictal ISA was observed in the majority of IS. Trends were observed suggesting that the presence of exclusive g-ISA changes may be a positive prognostic factor in IS.

Predictive value of EEG findings at control of epileptic spasms for seizure relapse in patients with West syndrome.

PURPOSE: To evaluate the prognostic importance of electroencephalography (EEG) findings at cessation of epileptic spasms for seizure outcome. METHODS: We reviewed 71 children with West syndrome (cryptogenic 14) who had obtained control of epileptic spasms with initial treatment (adrenocorticotropic hormone (ACTH) 37, high-dose vitamin B6 2, and antiepileptic drugs 32). According to the EEG findings at control of epileptic spasms, the subjects were divided into three groups: normal group (no epileptic activity, n=12), abnormal group (residual epileptic activity without hypsarrhythmia, n=53), and hypsarrhythmic group (persisting hypsarrhythmia, n=6). RESULTS: Overall, 47 (66%) of the 71 patients (cryptogenic 4) had experienced relapses of seizures (epileptic spasms 23 and focal seizure 24) after initial control of epileptic spasms. Within symptomatic cases, seizure relapse rate varied widely from 0% (Down syndrome) to 100% (tuberous sclerosis), depending on underlying causes. Seizure relapse depended on the EEG findings at control of epileptic spasms. The normal group had a significantly lower seizure relapse rate (17%) in comparison with the abnormal group (75%), the hypsarrhythmic group (83%), and the epileptiform (abnormal plus hypsarrhythmic, 76%) group. No significant difference in seizure relapse rate was observed between non-hypsarrhythmic (normal plus abnormal, 65%) and hypsarrhythmic groups. At the last follow-up, normal group children also showed a favorable seizure prognosis (seizure control 100%). CONCLUSIONS: A favorable seizure prognosis is associated with the disappearance of epileptic activity, but not the resolution of hypsarrhythmic pattern on EEG at control of epileptic spasms. We suggest that effective treatment for West syndrome should produce both cessation of epileptic spasms and disappearance of epileptic activity on EEG.

Polyunsaturated fatty acid-enriched diet therapy for a child with epilepsy.

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with an established efficacy for treating medically refractory epilepsy in children. Fatty acids are the most important constituent of the KD in all aspects of efficacy and complications. Among fatty acids, polyunsaturated fatty acids (PUFAs) increase anticonvulsant properties and reduce the complications associated with the high-fat diet. Here, we report a 7-year-old boy with Lennox-Gastaut syndrome combined with mitochondrial respiratory chain complex I deficiency, whose medically intractable seizures have been successfully controlled with a PUFA-enriched modified Atkins diet without any significant adverse events. The diet consists of canola oil and diverse menu items like fish and nuts instead of olive oil and has an ideal 1:2.8 ratio of omega-3 to omega-6. In addition, fractionation of this boy's plasma showed normal levels of fatty acids, including omega-3 (alpha-linoleic acid, eicosapentaenoic acid) and omega-6 (linoleic acid, arachidonic acid) as well as monounsaturated fatty acids (oleic acid). Plasma docosahexanoic acid remained low after PUFA-enriched diet therapy. PUFA-enriched diet therapy is likely to increase the efficacy of diet therapy and reduce complications of a high-fat diet in children with refractory epilepsy.

lennox-Gastaut syndrome: an updateon treatment.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy. Few current treatment options are effective in improving seizure control. This paper reviews the available treatments of LGS and discusses a new option in Canada, rufinamide. It is a wide spectrum anticonvulsant, approved in a number of countries for the treatment of LGS. In a randomized controlled trial in the LGS population, adjunctive rufinamide therapy has been shown to offer significantly greater reduction in total seizure frequency and tonic-atonic seizure frequency in comparison to placebo. Efficacy has been assessed over three years and appears to be sustained. Most adverse events were cognitive (e.g. somnolence) or gastrointestinal in nature and in many cases transient or mild. based on the efficacy and safety data on rufinamide obtained to date, this medication will provide additional benefits to patients with LGS in Canada and is an important consideration for our patients in the adjunctive treatment setting.

Update on the management of Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is a severe childhood epilepsy disorder characterized by encephalopathy and multiple, often intractable, seizure types. The drop attack is the most frequently recognizable seizure type in this patient population, and is also the most dangerous physically, thus severely limiting quality of life. The diagnosis is confirmed by electroencephalography, for which the classic pattern is a slow 2.5 Hz generalized spike-and-wave. Newer pharmacologic treatments include rufinimide and clobazam. However, antiepileptic drugs are often exhausted in pursuit of seizure control requiring nonpharmacologic interventions. These include dietary therapies, vagus nerve stimulation, and epilepsy surgery, including corpus callosotomy and focal curative resection. Although large lobar resections are often required, very localized, discrete resections may be possible, as in symptomatic Lennox-Gastaut syndrome (specifically, hypothalamic hamartoma). We review the history of the disease and current management options.

EEG-fMRI reveals activation of brainstem and thalamus in patients with Lennox-Gastaut syndrome.

PURPOSE: Even if etiologies of Lennox-Gastaut syndrome (LGS) are diverse, the multiple causes converge into a final common pathway that results in this specific epilepsy phenotype. There is little knowledge, however, about neuronal networks that may be a part of this pathway. METHODS: To investigate these networks, 11 children with LGS and 9 control children with multifocal epileptic activity were investigated using simultaneous recordings of EEG and functional MRI (EEG-fMRI) in a 3 Tesla scanner. KEY FINDINGS: Individual and group analyses revealed significant activation of brainstem and thalamus (especially centromedian and anterior thalamus) associated with epileptiform discharges in patients with LGS. None of the patients with multifocal epileptic activity presented with the same hemodynamic activation pattern. SIGNIFICANCE: Because brainstem activation has been associated with infantile spasms, which often evolve into LGS, and thalamus activation has been observed in patients with primary (idiopathic generalized syndromes) and secondary (focal epilepsies) bilateral synchrony, the described network in LGS may represent the common pathogenetic pathway of these different conditions.

West syndrome in an infant with vitamin B12 deficiency in the absence of macrocytic anaemia.

Vitamin B(12) deficiency in infants often produces haematological and neurological deficits, including macrocytic anaemia, neurodevelopmental delay or regression, irritability, weakness, hypotonia, ataxia, apathy, tremor, and seizures. The diagnosis of vitamin B(12) deficiency can be difficult when the typical macrocytic anaemia is absent. We report the case of a 10-month-old female diagnosed with West syndrome associated with vitamin B(12) deficiency but without macrocytic anaemia caused by nutritional inadequacy in the mother. The patient's motor skills and cognitive development were normal until she was 9 months old, when she began to exhibit a series of sudden flexions of the head, trunk, arms, and legs. She was exclusively breast-fed and had received no vitamin supplementation. Results of electroencephalography (EEG) indicated modified hypsarrhythmia and the patient was diagnosed as having West syndrome. Synthetic adrenocorticotropic hormone was administered and although her spasms had resolved, the patient remained apathic and could not sit without assistance. EEG results indicated generalized slow activity. After she was diagnosed as having vitamin B(12) deficiency, parenteral treatment with vitamin B(12) was initiated. Her symptoms resolved and EEG was completely normal. When she was 20 months old she exhibited an age-appropriate developmental and neurological profile. To our knowledge, this is the first report of West syndrome as a presenting symptom of vitamin B(12) deficiency.

A case of Pallister-Killian syndrome associated with West syndrome.

We report the case of a 19-month-old boy with Pallister-Killian syndrome associated with West syndrome. The child was born at term to a healthy mother after an uneventful pregnancy. He was born by cesarean section because of fetal macrosomia. He was observed to have nystagmus, craniofacial dysmorphism, and mental retardation. Intractable epileptic spasms developed 17 months after birth, and electroencephalography revealed a modified hypsarrhythmia. The seizures were uncontrollable with sodium valproate monotherapy. At the age of 19 months, the child was diagnosed with Pallister-Killian syndrome of mosaic tetrasomy 12p by fluorescence in situ hybridization. Combination treatment with high-dose pyridoxal phosphate and sodium valproate eliminated seizures and improved the electroencephalographic abnormalities. To our knowledge, this is the first reported case of Pallister-Killian syndrome associated with West syndrome.

Different neuronal networks are associated with spikes and slow activity in hypsarrhythmia.

PURPOSE: West syndrome is a severe epileptic encephalopathy of infancy characterized by a poor developmental outcome and hypsarrhythmia. The pathogenesis of hypsarrhythmia is insufficiently understood. METHODS: We investigated eight patients with infantile spasms and hypsarrhythmia (group I) and 8 children with complex partial seizures (group II) using simultaneous recordings of electroencephalogram (EEG) and functional MRI. Hemodynamic responses to epileptiform discharges and slow wave activity (EEG delta power) were analyzed separately. RESULTS: In group I (mean age, 7.82 +/- 2.87 months), interictal spikes within the hypsarrhythmia were associated with positive blood oxygenation level-dependent (BOLD) changes in the cerebral cortex (especially occipital areas). This was comparable with cortical positive BOLD responses in group II (mean age, 20.75 +/- 12.52 months). Slow wave activity in group I correlated significantly with BOLD signal in voxels, which were localized in brainstem, thalamus, as well as different cortical areas. There was no association between BOLD effect and EEG delta power in group II. Moreover, as revealed by group analysis, group I differed from group II according to correlations between BOLD signal and slow wave activity in putamen and brainstem. CONCLUSIONS: This study demonstrates that multifocal interictal spikes and high-amplitude slow wave activity within the hypsarrhythmia are associated with the activation of different neuronal networks. Although spikes caused a cortical activation pattern similar to that in focal epilepsies, slow wave activity produced a hypsarrhythmia-specific activation in cortex and subcortical structures such as brainstem, thalamus, and putamen.

West syndrome in a patient with balanced translocation t(X;18)(p22;p11.2).

We describe a case of West syndrome with the balanced translocation t(X;18)(p22;p11.2). Treatment with high-dose vitamin B6, adrenocorticotropic hormone, thyrotropin-releasing hormone, and antiepileptic compounds was not effective, and the patient exhibited persistent refractory seizures and severe developmental delays. Although no mutation analysis and X chromosome inactivation were performed, we suggest that the chromosomal abnormality in the present patient is the main etiologic factor responsible for the infantile spasms and severe developmental delay.

A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia.

We report a 2-month-old male with West syndrome associated with infantile hypophosphatasia. The male infant was born at term to a healthy mother after an uneventful pregnancy. He was born by cesarean section because of breech presentation. He was observed to have short extremities, and radiographs were consistent with achondroplasia. The serum alkaline phosphatase level was 2 IU/dL. Intractable tonic seizures developed 2 days after birth, and an electroencephalogram revealed a burst-suppression pattern for the first 2 months of life. The seizures were uncontrollable with conventional antiepileptic drugs. At the age of 2 months, he had a series of infantile spasms, and the electroencephalogram indicated hypsarrhythmia. Treatment with high-dose pyridoxal phosphate eliminated his seizures.

Infantile spasms and Lennox-Gastaut syndrome.

Infantile spasms and Lennox-Gastaut syndrome are rare but are important to child neurologists because of the intractable nature of the seizures and the serious neurologic comorbidities. New antiepileptic drugs offer more alternatives for treating both infantile spasms and Lennox-Gastaut syndrome. Selected children with infantile spasms are candidates for epilepsy surgery. Vagus nerve stimulation, corpus callosotomy, and the ketogenic diet are all options for selected children with Lennox-Gastaut syndrome. The epidemiology, clinical manifestations of the seizures, electroencephalographic characteristics, prognosis, and treatment options are reviewed for infantile spasms and Lennox-Gastaut syndrome. Additional therapies are needed for both infantile spasms and Lennox-Gastaut syndrome as many children fail to achieve adequate seizure control in spite of newer treatments.

High-dose vitamin B(6) treatment in West syndrome.

Approximately 10-30% of patients with West syndrome respond to high-dose vitamin B(6) treatment. The response to vitamin B(6) is rapid; seizures disappear within the first 2 weeks of treatment. Mild side effects, such as gastrointestinal symptoms and liver dysfunction, are observed in 40-70%, but these resolve after discontinuation or a reduction of the dosage of vitamin B(6). High-dose vitamin B(6) treatment is useful as a first line agent in treating West syndrome.

Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings.

Clinical experience with the treatment of 3-phosphoglycerate dehydrogenase deficiency, a rare inherited disorder of serine synthesis, is scarce. We report on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was found to be normocephalic at birth and showed moderate delay of white matter myelinisation, while her seizures arrested spontaneously even without treatment. In the younger sister with the classical phenotype, feeding difficulties with recurrent gastro-oesophageal reflux prompted us to treat her temporarily with high-dose serine (1400 mg/kg/day). An arrest of head growth then occurred but could be reversed by reducing the serine supply. In both children serine therapy was associated with decreased concentrations of methionine, isoleucine, and ornithine in the cerebrospinal fluid, attributed to competitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstrate that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogenase deficiency. An adverse effect of high-dose serine therapy on head growth and on the transport of neutral amino acids across the blood-brain barrier should be considered and requires adjustment of treatment.

Zonisamide monotherapy in newly diagnosed infantile spasms.

PURPOSE: We determined the short-term efficacy of zonisamide (ZNS) monotherapy in newly diagnosed patients with infantile spasms (IS). METHODS: Eleven hospitals participated in this open, prospective trial. ZNS 3-10 mg/kg/day was administered as the second-choice drug to 11 newly diagnosed patients with IS (cryptogenic 3, symptomatic 8) who failed to respond to high-dose vitamin B6. RESULTS: Four infants with symptomatic IS had cessation of spasms and disappearance of the hypsarrhythmia. In these responders, the spasms ceased after a few days (1-5 days) of treatment at a dose of ZNS 4-5 mg/kg/day which produced plasma ZNS concentrations ranging from 5.2 to 16.3 microg/ml (mean 9.8 microg/ml). There were two relapses (50%) 4-6 weeks after cessation of seizures, however. Relapse was predicted by effects of ZNS on EEG; the 2 infants in whom an abnormal EEG persisted had relapses, whereas the 2 whose EEG normalized remained seizure-free (follow-up 20 and 26 months). No adverse reactions were noted. CONCLUSIONS: ZNS may be effective in the initial treatment of selected patients with IS.

Focal spasms in clusters, focal delayed myelination, and hypsarrhythmia: unusual variant of West syndrome.

We report a patient who began to have clusters of seizures characterized by brief elevation of the right arm at 6 months of age. An interictal electroencephalogram (EEG) at 7 months revealed hypsarrhythmia without definite asymmetry. Simultaneous EEG and video recording disclosed that these focal spasms were associated with fast wave bursts superimposed on slow waves most markedly in the left centro-midtemporal region. The patient became seizure-free after synthetic ACTH therapy. The patient is developmentally normal at 3 years 5 months, but magnetic resonance imaging studies revealed findings suggestive of delayed myelination in the left frontal region. This patient is considered to have had an unusual variant of West syndrome associated with focal delayed myelination.