Study of the Mozart Effect in Children with Epileptic Electroencephalograms

PURPOSE: To establish if listening to Mozart’s Sonata for two pianos in D major (K448) has an anti-epileptic effect on the EEGs (electroencephalograms) of children.

METHODS: Forty five children (2-18 years; mean 7 years 10 months) who had epileptiform activity on EEG were recruited from those attending for scheduled EEG investigations. Mozart’s Sonata for two pianos in D major (K448) and an age-appropriate control music were played during the EEG. There were five consecutive states during the record, each lasting 5?min; before Mozart music (baseline), during Mozart music, after Mozart music/before control music, during control music and after control music. Epileptic discharges were counted manually and the mean frequency of epileptic discharges calculated in each state.

RESULTS: A significant reduction (p?<?0.0005) in the frequency of epileptic discharges was found during listening to the Mozart music compared to the baseline. No evidence of a difference in mean epileptic discharges was found between the baseline and the other three states or between listening to the Mozart music and control music.

CONCLUSION: This study confirms an anti-epileptic effect of Mozart music on the EEG in children, which is not present with control music. The role of ‘Mozart therapy’ as a treatment for drug-resistant epilepsy warrants further investigation.

Study: Major Depressive Disorder in Epilepsy Clinics – A Meta-Analysis

BACKGROUND AND PURPOSE: Although depression is a frequent psychiatric comorbidity in people with epilepsy (PWE), its prevalence has been underestimated. Comorbid depression has negative impacts on treatment outcomes and quality of life (QOL). It also causes various problems in PWE, such as fatigue, irritability, and suicidality. This meta-analysis was performed to estimate the frequency of major depression disorder (MDD) in clinics managing PWE.

METHODS: We searched MEDLINE, EMBASE, Cochrane Library, Web of Science, and SCOPUS to identify studies. Hospital-based studies and original research presenting information regarding prevalence of MDD, determined using a gold standard diagnostic tool in adult PWE, were considered for inclusion. The prevalence of depression was examined by meta-analysis. In addition, subgroup analysis was performed based on the continent where the selected studies were conducted, the strictness of selection criteria, and gender. Strict selection criteria were defined as any mention of the use of exclusion criteria.

RESULTS: A total of 6607 studies were identified by searching the five databases outlined above. After screening and rescreening, 35 studies were included in the meta-analysis. The total number of PWE was 5434. In the test for heterogeneity of the studies, I2 was 68.014, and the Cochran Q value was 106.296 (p?<?0.01). As a pooled estimate, the point prevalence of MDD in PWE was 21.9% with a 95% confidence interval (CI) of 20.8-23.0 in a fixed effects model. In subgroup analyses, continent partly explained the heterogeneity among the selected studies, but the strictness of selection criteria did not. The prevalence of MDD was higher in females than in males (26.4% vs. 16.7%, respectively) with an odds ratio (OR) of 1.805 (95% CI: 1.443-2.258; p?<?0.01).

CONCLUSIONS: The point prevalence of major depressive disorder is estimated at 21.9% among people with epilepsy in epilepsy clinics and is higher in females than in males. Based on this relatively high prevalence in people with epilepsy, measures are required to identify and resolve MDD. In addition, the female predominance of major depressive disorder among people with epilepsy indicates a need to pay greater attention to females. Such efforts may reduce the impact of depression in people with epilepsy and improve their quality of life.

Study: Risk Assessment of In-Hospital Mortality of Patients with Epilepsy – A large Cohort Study

PURPOSE: This study aimed to explore the mortality risks of hospitalized patients with epilepsy (PWE).

METHODS: Our data source was extracted from discharge abstracts in a hospital medical database. Various clinical variables, including demographical characteristics, natural features of epilepsy, and comprehensive set of comorbidities, were screened to investigate the risk. Comorbidities were defined using a validated ICD-10-based classification. The distributions of comorbid conditions and demographics were presented. In-hospital mortality rates of groups with epilepsy and without epilepsy were compared. Logistic regression was applied to explore the important predictors of in-hospital mortality.

RESULTS: A cohort of 11,422 PWE (male: 58.5%, mean age: 40.2?years) was recruited for the study. The most common comorbidities were cerebrovascular disease, hypertension, and peripheral vascular disease, which accounted for 23.5%, 18.8%, and 8.0% of the study cohort, respectively. In-hospital mortality rates were 2.9% and 1.1% in the epilepsy and nonepilepsy cohort, respectively. Male patients exhibited an increased risk of death (odds ratio (OR)?=?1.2; 95% confidence interval (CI)?=?1.0-1.6). Patients aged over 65?years were more likely to die than those below 18?years (OR?=?18.2; 95% CI?=?8.8-31.0). Patients with comorbidities, including central nervous system (CNS) infections, renal disease, traumatic brain and head injuries, anoxic brain injury, metastatic cancer, pulmonary circulation disorders, encephalopathy, solid tumor without metastasis, cardiac arrhythmias, and diabetes without complication, had a higher risk of in-hospital death than patients without comorbidities.

CONCLUSION: The in-hospital mortality of people with epilepsy increased remarkably with age, and this parameter was predominant in male patients. Central nervous system infection, renal disease, traumatic brain and head injuries, anoxic brain injury, metastatic cancer, pulmonary circulation disorders, encephalopathy, solid tumor without metastasis, cardiac arrhythmias, and diabetes without complication were the most important comorbidities associated with in-hospital death.

Special ILAE Report: Genetic Generalized Epilepsies

The genetic generalized epilepsies (GGEs) are mainly genetically determined disorders. Although inheritance in most cases appears to be complex, involving multiple genes, variants of a number of genes are known to contribute. Pathogenic variants of SLC2A1 leading to autosomal-dominant GLUT1 deficiency account for up to 1% of cases, increasing to 10% of those with absence seizures starting before age 4 years. Copy number variants are found in around 3% of cases, acting as risk alleles. Copy number variation is much more common in those with comorbid learning disability. Common variant associations are starting to emerge from genome-wide association studies but do not yet explain a large proportion of GGEs.

Although currently genetic testing is not likely to yield a diagnosis for most patients with GGEs, it can be of great importance in specific clinical situations. Providers should consider the individual patient’s history in determining the utility of genetic testing.

Mayo Clinic Uses An mHealth App to Identify Epileptic Seizures

study conducted by the Mayo Clinic in Arizona has found that an mHealth app can be used to diagnose epilepsy. It’s one of several mobile health tools being used to manage care for people with chronic conditions.

The EpiFinder app reportedly correctly identified epilepsy or offered an accurate alternative diagnosis in almost 87 percent of the cases during a recent study at the Mayo Clinic’s Department of Neurology.

The app analyzes data entered into the platform by either the patient or a care provider. Its creator, Neel Mehta, says the tool can be used by either a doctor or a consumer.

It’s one of several mHealth tools being used to improve care management for people living with epilepsy.

This past February, the U.S. Food and Drug Administration approved a wearable, called the Embrace, that can detect the onset of a serious epileptic seizure and alert care team members. And last year, Johns Hopkins University announced the completion of a 10-month study during which researchers remotely monitored some 600 people with epilepsy through the EpiWatch app on their Apple Watches, enabling them to gather data on epileptic seizures and daily care.

Clinical Trial: AMO-01 to Treat Adolescents and Adults With Phelan-McDermid Syndrome (PMS) and Co-Morbid Epilepsy

Brief Summary: The purpose of this study is to investigate the safety, tolerability and efficacy of a single 6-hour intravenous infusion of AMO-01 to treat adolescents and adults with Phelan-McDermid Syndrome (PMS) and co-morbid epilepsy. Phelan-McDermid Syndrome (PMS) is a neurodevelopmental disorder characterized by a chromosomal deletion or mutation at 22q13.3 that contains the SHANK3/ProSAP2 gene. A key co-morbidity in PMS is the presence of epilepsy.

Currently there are no approved treatments for PMS. Furthermore, there has been relatively little clinical study of pharmacological interventions for PMS. AMO-01 may provide benefit to PMS patients exhibiting behavioral abnormalities and seizures.

Estimated study start date: May 31, 2018
Estimated study completion date: March 31, 2019

Eligibility Criteria

Ages Eligible for Study: 12 Years to 45 Years (Child, Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Subjects under study must have a diagnosis of Phelan McDermid syndrome (PMS) with genetic confirmation of pathogenic SHANK3 deletion or mutation.
  • Subjects must be post pubertal males or females aged ?12 years and ?45 years at screening.
  • Subject must have a diagnosis of epilepsy with a witnessed seizure event in the 28 days prior to screening and an approximate minimum of four seizures monthly in the 6 months preceding the screening.
  • Subjects must have a syndrome-specific Clinical Global Impression-Severity Score of 4 or greater at screening
  • Subject’s parent or legally authorized representative (LAR) must provide written informed consent before any study related procedures are conducted. Where a parent or LAR provides consent, there must also be assent from the subject (as required by local regulations).
  • Subject’s caregiver must be willing and able to support the subject’s participation for the duration of the study.
  • Subject’s caregiver is able and willing to maintain an accurate and complete daily written seizure diary for the entire duration of the study.

 

Exclusion Criteria:

  • Receiving medications/therapies not stable (i.e. changed) within 4 weeks prior to screening. For each enrollee, every effort should be made to maintain stable regimens of allowed concomitant medications and allowed non-medicine based therapies throughout the course of the study, from screening until the last study assessment.
  • Known hypersensitivity to farnesylated dibenzodiazepinone or any of the formulation components.
  • Subjects with a history of uncontrolled hypotension or hypertension (Polysorbate 80 is a major constituent of AMO-01 and can cause hypotension).
  • Subjects that have received Coumadin or heparin in the 2 weeks preceding screening.
  • Medical illness or other concern which would cause the investigator to conclude that the subject will not be able to perform the study procedures or assessments or would confound interpretation of data obtained during assessments.
  • Females who are pregnant, lactating, or not willing to use a protocol-defined acceptable contraception method if sexually active and not surgically sterile.
  • Males, engaged in sexual relations with a female of child bearing potential, not using an acceptable contraception method if sexually active and not surgically sterile.
  • Clinically significant abnormalities in safety laboratory tests, vital signs or ECG, as measured at Screening (may repeat to confirm).
  • Current clinically significant (as determined by the investigator) neurological, cardiovascular, renal, hepatic, endocrine or respiratory disease that may impact the interpretability of the study results.
  • Current clinically significant (as determined by the investigator) lymphedema that may compromise venous access and/or may have an adverse impact on study drug distribution and clearance.
  • Judged clinically to be at risk of suicide by the investigator.
  • Average QTcF value of >450 msec at Screening (may repeat to confirm).
  • Subjects in whom an indwelling intravenous line could not be established or maintained.

Engage Therapeutics Doses First Patient In Phase 2b Trial Of Epilepsy Seizure Rescue Therapy Staccato® Alprazolam

Engage Therapeutics, Inc. announced May 4th the dosing of the first patient in its multi-center, double-blind, randomized Phase 2b StATES (Staccato®AlprazolamTerminatesEpilepticSeizures) trial to investigate the safety and efficacy of Staccatoalprazolam in subjects with epilepsy that have a predictable seizure pattern.

The StATES trial (NCT03478982) will enroll 108 patients across 40 U.S.-based clinical sites. The primary endpoint is the cessation of seizure activity. Seizure episode severity, as well as the incidence of adverse events, will also be evaluated. Topline data is expected in the second half of 2019.Staccatoalprazolam, a single use, investigational epileptic seizure rescue therapy, combines the Staccato delivery technology, which is currently used in a U.S. Food and Drug Administration (FDA)-approved product, with alprazolam, an FDA-approved benzodiazepine. Together, this combination is novel for an epilepsy application in a patient population in need of innovative rescue options.

Greg Mayes, president, CEO and founder of Engage Therapeutics, said, “For individuals with epilepsy that have a predictable seizure pattern, currently available rescue treatments can only address the prevention of seizure activity once the first seizure ends, but Staccato alprazolam has the potential to be the first and only product that can abort an active seizure. We are excited by the enthusiastic response that this study has received from the epilepsy community and how quickly we have been able to advance this promising candidate to this point in development.”

CURE Discovery: Genetic Research Finds Potential Alternatives to Brain Surgery for Children with Cortical Dysplasia

A Potential Alternative is Already in Clinical Trial

Recent research by CURE grantee Dr. Jeong Ho Lee of the Korea Advanced Institute of Science and Technology has shed important light on the genetic mutations that lead to focal cortical dysplasia, a severe form of pediatric epilepsy that inadequately responds to available treatment options. Genetic mutations were found in the brain tissue of individuals affected by a particular subtype of focal cortical dysplasia (focal cortical dysplasia type II) that is characterized by brain abnormalities, leading to seizures and epilepsy.

Conventional genetic testing methods to identify genetic mutations in those with epilepsy often use blood or saliva from patients. However, these latest results from Dr. Lee and his team suggest that certain epilepsy-related gene mutations may only be detectable when brain tissue is analyzed.

Brain-Only Mutations in Genes that Cause Focal Cortical Dysplasia

By comparing blood and saliva samples to samples of brain tissue from a group of 40 individuals who had previously undergone brain surgery for focal cortical dysplasia type II, Dr. Lee and his team found that a significant number of these individuals (12.5%) had brain-only mutations in genes TSC1 and TSC2. Together with the previous pioneering work of his team to identify brain-only mutations in the MTOR gene in individuals with focal cortical dysplasia type II, they revealed that brain-only mutations in genes within the mTOR brain signaling pathway (including the genes TSC1, TSC2 and MTOR) are found in up to 30% of individuals with focal cortical dysplasia. The fact that these mutations were found only in the brain means that these mutations would be undetectable by conventional genetic testing methods, suggesting that investigation of brain-only mutations should be explored to a greater extent.

In addition to identifying brain-only mutations leading to focal cortical dysplasia, Dr. Lee and his team also addressed the current lack of adequate animal models to better study the disorder. The team was able to successfully recreate the brain-only mutations in genes TSC1 and TSC2 in developing mice, providing a much-needed animal model for further examination of the ways in which gene mutations can lead to focal cortical dysplasia type II.

Clinical Trials for the Treatment of Focal Cortical Dysplasia

Furthermore, the team provided evidence that mTOR inhibitors, such as rapamycin or everolimus, are promising anti-epileptic drugs for the treatment of focal cortical dysplasia. In fact, everolimus is currently under phase II clinical trial for the treatment of focal cortical dysplasia.

As noted by Dr. Lee, because focal cortical dysplasia is a drug-resistant epilepsy, many children with the disorder require invasive brain surgery as treatment. However, even in cases where surgery is performed, up to 40% of these children may still have seizures. By identifying genes associated with focal cortical dysplasia as well as creating a new way of studying the genetic mechanisms behind the disorder, Dr. Lee and his team have made progress towards the creation of novel, non-surgical targets at which to aim treatments for this devastating form of drug-resistant childhood epilepsy.

[1] Lim et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Human Genet 2017; 100(3):454-472.
[2] Guerrini et al. Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 2015; 56(11):1669-86.
[3] Gaitanis and Donahue. Focal cortical dysplasia. Ped Neurol 2013; 49:79-87.
[4] Poduri et al. Genetic testing in the epilepsies – developments and dilemmas. Nat Rev Neurol 2014; 10(5):293-299.
[5] Lim et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21(4):395-400.

Historical Article: Classification of Epilepsies in the 18th Century

Classifications provide “a framework on which to conceptualize knowledge and research” through organisation of items according to their fundamental relationships; they also allow standardised communication among the scientific community, and they tailor patient-oriented treatment decisions.

Throughout history, several attempts have been made to organise epileptic seizures and epilepsies into clinical categories for diagnostic purposes, epilepsy research, development of antiepileptic therapies, and communication around the world. The International League Against Epilepsy has made several proposals of classification from 1969 onwards, culminating in a new epilepsy classification (2017). This article provides historical perspective on the classification of epilepsies in the 18th century.

Study: Sleep Architecture and Epileptic Characteristics of Drug Naïve Patients in Childhood Absence Epilepsy Spectrum – A Prospective Study

PURPOSE: Childhood absence epilepsy (CAE) is an epileptic syndrome presenting between 2nd-10th years. The spells are elicited with hyperventilation (HV) while sleep seems to exacerbate the electrical activity. Our aim is to describe sleep architecture and its relationship with epileptic discharges (EDs) in patients with CAE, before treatment and one year later.

METHODS: Twenty-eight, drug-naive children were recruited (21 girls), mean age 90.1?±?32.6?months. Routine-EEG and overnight EEG-polygraphy were conducted upon diagnosis and one year later. Patients were separated in two groups of similar mean age, according to their clinical response at the second recording: group A: children with absolute control of absences and group B: children with partial control. Sleep parameters, EDs and arousals were measured. The effect of medication on sleep parameters was examined, according to 2 groups: valproic-treated and non valproic-treated.

RESULTS: Group A showed significant improvement in total sleep time, REM-sleep latency, REM-sleep, arousals-number/hour and arousals-duration/hour between the two recordings. Comparing the two groups for each recording separately, group A initially demonstrated greater epileptic activity and worse sleep parameters, whereas in the second recording exhibited total elimination of the EDs and significantly less arousals. Group B demonstrated persisting EDs and slight deterioration in some sleep parameters during the second recording, despite the lower epileptic load initially. No significant difference was identified between valproic and non-valproic treated patients, regarding the effect on sleep parameters.

CONCLUSION: Absolute control of absences and normalization of the electroencephalogram are accompanied by more continuous, stable and efficacious sleep in children with CAE.