TSC Research Article Summaries: Seizures

Resection of ictal high frequency oscillations is associated with favorable surgical outcome in pediatric drug resistant epilepsy secondary to tuberous sclerosis complex.

Fujiwara H, Leach JL, Greiner HM, Holland-Bouley KD, Rose DF, Arthur T, Mangano FT
Epilepsy Research, 2016 Oct;126:90-7
DOI: 10.1016/j.eplepsyres.2016.07.005

What is the topic?

Tuberous sclerosis complex (TSC) is a syndrome that is characterized by the presence of benign tubers in multiple parts of the body. A vast majority of individuals with TSC exhibit seizures, and a proportion of these individuals do not respond to conventional anti-seizure medications. In these cases, resection (i.e. removal of the part of the brain that produces seizures) is helpful in reducing seizure frequency. Since most people with TSC have multiple tubers, it is difficult to decide what tuber is causing the seizure activity and should be removed. The thought in the field is that in such cases, the biggest tubers should be resected. However, a subset of people with TSC does not show one dominant tuber, and conventional MRI and EEG are not able to guide surgeons as to what tuber to remove.

Studies have found that high frequency oscillations (HFOs; waveforms in the brain 80Hz and above) give a good indication about the seizure-onset zone in children and adults with epilepsy. The authors of this study wanted to know whether HFOs can be used in TSC as well as a marker to guide surgery.

What did the researchers hope to learn?

By examining the intracranial EEG data of children with TSC who had refractory epilepsy, the researchers wanted to know if HFOs can be a more sensitive marker of the seizure-onset zone. If so, HFOs can be used to guide resection surgery.

Who was studied?

Fourteen children with TSC and refractory (drug resistant) epilepsy were studied. Children were anywhere from 2 to 16 years old.

How was the study conducted?

The researchers implanted EEG electrodes in the subdural space of children and studied HFOs. Resection surgery was conducted, and post-operative follow-up was done. The researchers took the HFO data, and examined whether HFOs correlate to MRI findings and to clinical outcome after surgery.

What did the researchers find?

All children in this study had HFOs during the start of the seizure. The exciting finding was that irrespective of the MRI findings, removal of the area that caused the HFOs led to a better outcome. That is, regardless of the way the tubers looked, complete resection of the part of the brain that produced HFOs was linked to better clinical outcome.

What were the limitations of the study?

There are technical challenges with using intracranial EEG recording – the number of electrodes in the grid is limited, and it could be that the researchers failed to get a complete picture of where HFOs were arising from.

What do the results mean for you?

This study showed that HFOs are a good biomarker of the epileptogenic zone in TSC as well, and a complete resection of the HFO-producing area led to best clinical outcome. Hence, it could be that larger resections aren’t necessarily better, but complete removal of the HFO-producing structure is more reliable and advantageous.

This summary was written by Sloka Iyengar, PhD, a neuroscientist and science writer based in New York (September 2016).

Resective Epilepsy Surgery for Tuberous Sclerosis in Children: Determining Predictors of Seizure Outcomes in a Multicenter Retrospective Cohort Study

Aria Fallah, MD, MSc, Shaun D. Rodgers, MD, Alexander G. Weil, MD, Sumeet Vadera, MD, Alireza Mansouri, MD, Mary B. Connolly, MD, Philippe Major, MD, Tracy Ma, MD, Orrin Devinsky, MD, Howard L. Weiner, MD, Jorge A. Gonzalez-Martinez, MD, PhD, William E. Bingaman, MD, Imad Najm, MD, Ajay Gupta, MD, John Ragheb, MD, Sanjiv Bhatia, MD. Paul Steinbok, MBBS, Christopher D. Witiw, MD, Elysa Widjaja, MD, MPH, O. Carter Snead, MD, James T. Rutka, MD, PhD
Neurosurgery, Volume 77 (4); 517-524, October 2015.
DOI 10.1227/NEU.0000000000000875

What is the topic?

Tuberous sclerosis complex (TSC) is a leading cause of genetic epilepsy, TSC presents with seizures in almost 90% of children. While antiepileptic medication has provided epileptic relief or “seizure freedom” in patients, only one-third of them ever actually achieve this.

In such cases where the disorder is refractory to medication, epilepsy surgery has been shown to be effective in providing seizure freedom or marked improvement in seizure control. The goal of the surgery is to identify and safely remove those regions of the brain responsible for generating abnormal electrical signals causing the seizures. These regions of the brain together comprise what is referred to as the epileptogenic zone (EZ).

However, it is unclear to what extent is resective surgery efficacious at curing the epilepsy.  Earlier studies have several limitations including small sample sizes, single-center reports leading to bias, inclusion of various etiologies of epilepsy and short duration of follow-up.   Therefore, there is poor generalizability of the results of these studies.

What did the researchers hope to learn?

As a multicenter, international study, the researchers sought to accurately quantify the probably of seizure freedom and identify important independent predictive variables that are associated with a successful surgical outcome and prolonged seizure freedom.

This information can inform pre-surgical discussions between the clinicians and families and influence the surgery that is performed to optimize seizure outcomes.

Who was studied?

A retrospective observational study was performed in eligible children who had undergone resective epilepsy surgery at specialized pediatric epilepsy centers in Canada and the United States between January 2005 and December 2013. The 6 study centers include the Cleveland Clinic Foundation in Cleveland, Ohio, Miami Children’s Hospital in Miami, Florida, Sainte-Justine UHC in Montreal, Quebec, Canada, New York University Langone Medical Center in New York, New York, The Hospital for Sick Children in Toronto, Ontario, Canada, and British Columbia Children’s Hospital in Vancouver, British Columbia, Canada.

How was the study conducted?

The inclusion criteria for this study were: age younger than 19 years at the time of surgery, diagnosis of TSC, minimum of 1 follow-up after the first postoperative week, surgery performed January 2005 or later, and available seizure outcome data. Participants who had undergone “palliative” surgical procedures such as vagus nerve stimulation and removal of the corpus callosum were not included in this study as these are not “curative” procedures.

Data was obtained from each study site using electronic or hard copy medical records by a clinician. Patient privacy was protected as data was collected in a standardized spreadsheet in electronic format and sent to the coordinating center (Toronto) for central analysis.

Based on previous studies and expert opinions for identifying potential predictors of seizure outcomes, variables of interest included: demographics, history of illness, as well as neuropsychological, neurophysiological, and structural imaging tests.

Seizure outcome was ascertained using a time-to-event (TTE) measure, i.e, the amount of time it took for patients to experience their first seizure after surgery. Auras, seizures due to medication withdrawal, and seizures within the first week of surgery were not considered for the purposes of this study.

Given the rarity of the disease, the sample size was comprised of 93 participants using an alpha value of .05, a beta value of .10, and an estimation of 43 events. This enabled the researchers to have 90% power to detect a 90% increase in hazard rate for a given variable.

What did the researchers find?

Of the 74 patients (41 of which were male) that participated in the study from the original 93, the researchers found that on follow up, 65% were seizure free for 1 year, 50% were seizure free for 2 years, 45% for 3 years, and 43% for 4 years. The median time frame of seizure freedom was 2 years after surgery.

The researchers also found that when analyzing one variable at a time among the participants, three factors that were particularly noteworthy in predicting a longer period of freedom from seizures after surgery were those patients who: (1) were younger in age at seizure onset; (2) had areas of the brain surrounding the tuber also resected (as opposed to only removing the tuber itself); and (3) had a larger size of predominant tuber to begin with.

With these findings the researchers concluded that the EZ may in fact extend beyond the area of tuber and involve additional regions of the brain surrounding the tuber. In turn, removing these surrounding regions is likely to yield more seizure freedom compared to simply removing the tuber itself.

What were the limitations of the study?

There are several limitations in this study with respect to the quality of the data. While this study was conducted across multiple study sites, the rarity of the disease continues to limit achieving an larger sample size that may be needed to study additional variables that may not be captured in a smaller sample size. In addition, given this was a retrospective study, variables that can only be included from a prospective study with the potential for greater predictive powers were left out of the study.

Also, since a more extensive resection of the EZ was shown to be associated with a better seizure outcome than a partial resection of the EZ, the extent of resection is challenging to ascertain accurately as it is not always dictated in the surgical notes, and these data may be lost if not prospectively tracked.

Lastly, given that participants who have surgery are selected based on the judgment that they are likely to have a successful outcome, this may introduce the potential for selection bias as the criteria for having surgery may not be the same across institutions.

What do the results mean for you?

Given that this was a multicenter study of a relatively large sample of pediatric patients with TSC, it provides the strongest evidence to date for achieving seizure freedom from surgical resection.

This article represents a great beginning and serves as an important stepping-stone for future studies to enhance seizure freedom outcomes of surgical resection. Next steps would be to (1) create more uniform protocols for collecting data across institutions; (2) obtain follow-ups over a longer period of time for this patient population; (3) include additional clinical centers to expand the data captured; and (4) consider real-life experiences when resective surgery is frequently supplemented or substituted by interventions which are solely “palliative” and not “curative.”

In the mean time, the evidence suggests that consideration be given to larger resections than just the tuber itself when possible to optimize seizure outcomes.

This summary was written by UCLA medical student, Samuel Asanad, September 2016.

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomized, double-blind, placebo-controlled study

Jacqueline A. French, John A. Lawson, Zuhal Yapici, Hiroko Ikeda, Tilman Polster, Rima Nabbout, Paolo Curatolo, Petrus J. de Vries, Dennis J. Dlugos, Noah Berkowitz, Maurizio Voi, Severine Peyrard, Diana Pelove, David N. Franz
Lancet, Published online September 6, 2016.
DOI 10.1016/S0140-6736(16)31419-2

What is the topic?

Up to 85% of individuals with tuberous sclerosis complex (TSC) have epilepsy, often occurring in the first year of life as either focal seizures or infantile spasms.  Untreated early-onset seizures are associated with an increased risk of autism and intellectual disability. More than 60% of individuals with TSC and seizures do not achieve seizure control with standard treatment such as antiepileptic drugs, epilepsy surgery, ketogenic diet, and vagus nerve stimulation, compared to 30-40% of individuals with epilepsy who do not have TSC.

Early case reports and several small human clinical trials showed beneficial effects of mTOR inhibitors in seizure control in individuals with TSC and uncontrolled seizures.

Everolimus is an mTOR inhibitor approved for the treatment of renal angiomyolipoma and sub-ependymal giant cell astrocytoma (SEGA) in individuals with TSC.

This is the first large scale clinical trial to evaluate the use of an mTOR inhibitor for treatment of epilepsy.

What did the researchers hope to learn?

Novartis Pharmaceuticals Corporation sponsored this clinical trial to assess the effectiveness and safety of two doses of everolimus compared with a placebo (a pill that looks identical to the everolimus pill but doesn’t contain any medicine) as an add-on treatment for focal-onset seizures in tuberous sclerosis complex.

Who was studied?

A total of 366 individuals (190 men, 176 women) with a confirmed diagnosis of TSC and 16 or more seizures occurring during an 8-week baseline period were enrolled from 99 centers in 25 countries worldwide.   The age range of participants was 2 – 56 years old.

How was the study conducted?

This was a study with an initial 8-week baseline period, followed by an 18-week core phase, and a 48-week extension phase.   Participants had to be on a stable dose of one to three antiepileptic drugs (AEDs) for at least 12 weeks before random assignment to one of the three treatment groups in the core phase, which were 1) low exposure everolimus, 2) high exposure everolimus, or 3) placebo (a pill that looks identical to the low and high dose pills but doesn’t contain everolimus).

What does low and high exposure mean?

Study participants in the two everolimus treatment groups received study medication to reach a target trough (lowest level of drug in the body) concentration of everolimus of 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure).

All participants (or their legal representative) provided written informed consent before entering the baseline period.

Participants, study investigators, site personnel, and the Novartis study team were masked to treatment assignment.

Personnel in charge of drug supply, assignment of treatment group, and analysis of blood levels were not masked to treatment assignment.

During the baseline period, participants or their caregivers completed a seizure diary, recording seizure type and frequencies.  Because multiple seizures types are present in TSC, all seizures were considered to be focal in onset (that is starting in one area of the brain) unless an EEG confirmed a generalized onset (that is starts in all parts of the brain).

Random assignment to the three treatment groups was done within four age subgroups.

Blood concentrations were measured during the core phase to make sure that each participant’s blood level reached the target trough concentration of everolimus for their group.  The pharmacy, which was not masked to treatment assignment made the dose adjustments by dispensing study medication that would get participants to the target concentration.

Treatment continued until the end of the core phase unless there was loss of seizure control, an episode of status epilepticus, interruption of more than 7 days of one or more AED that the participant was on at baseline, intolerable side effects, or withdrawal of consent.

The Vineland Adaptive Behavior Scale was completed at baseline, at completion of the core phase, then every six months thereafter to assess the effect of everolimus on the participant’s behavior.

What did the researchers find?

346 of 366 participants (95%) completed the core phase.  Everolimus produced a significant reduction in seizure frequency in participants with treatment-resistant epilepsy and TSC compared with placebo. At baseline, nearly half of the participants had failed treatment with six or more previous AEDs. The results of this study showed an improvement in seizure control with everolimus among multiple seizure types.  The odds for response in participants treated with everolimus was over 2 times (low exposure group) and nearly 4 times (high exposure group) higher than with placebo.

The most common reason for treatment discontinuation was adverse events in all three groups.

The most common adverse events of any cause reported in more than 15% of participants in either of the everolimus treatment group included stomatitis (mouth sores), diarrhea, common cold, and fever.   Stomatitis was reported as severe or disabling in four participants (3%) in the low dose group and five participants (4%) in the high dose group.

What were the limitations of the study?

1. The results of this study showed short-term benefit of everolimus when added to best-available AED therapy during the core phase.  The effectiveness and safety from longer term exposure to everolimus therapy for epilepsy needs to be evaluated.
2. Due to the substantial intellectual disability among many of the study participants, the study investigators were unable to complete the behavior assessment at baseline, limiting the interpretation of results.

What do the results mean for you?

A person with TSC and frequent seizures of mixed types may experience a meaningful reduction in seizure frequency with everolimus that improves with ongoing treatment.

This summary was written by TSC Alliance staff, Jo Anne Nakagawa, Director of Clinical Projects and TSC Clinic Liaison, September 2016.

Downregulation of CD47 and CD200 in patients with focal cortical dysplasia type IIb and tuberous sclerosis complex

Fei-Ji Sun, Chun-Qing Zhang, Xin Chen, Yu-Jia Wei, Song Li, Shi-Yong Liu, Zhen-le Zang, Jiao-Jiang He,Wei Guo and Hui Yang
Journal of Neuroinflammation  2016 Apr 19;13(1):85
DOI: 10.1186/s12974-016-0546-2

What is the topic?

Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) in children are characterized by epilepsy. One reason for generation of seizures in these conditions is increased inflammation in the brain which is mediated by certain cells known as microglia and macrophages.  CD47 and CD200 are two proteins that act through their receptors SIRP-α and CD200R respectively, to inhibit inflammation in the brain. In this paper, the scientists examined the levels of CD47/SIRP-α and CD200/CD200R in brain tissue from patients with FCD IIb and TSC, and compared it to tissue from control subjects.

What did the researchers hope to learn?

By looking at levels of CD47/SIRP-α and CD200/CD200R in brain tissue from patients with FCD IIb and TSC, the scientists hoped to learn whether alterations in these proteins can contribute to seizures.

Who was studied?

12 subjects with FCD IIb, 13 with TSC and 6 control subjects were studied.

How was the study conducted?

Epileptogenic tissue was obtained from all subjects using magnetic resonance imaging (MRI). This was also confirmed later by neuropathology.

What did the researchers find?

The scientists found reduced levels of CD47/SIRP-α and CD200 proteins in brain tissue from individuals with FCD IIb and TSC, while no changes in CD200R expression were found.

What were the limitations of the study?

There is a shortage of studies like this one, where tissue from subjects with FCD IIb and TSC are studied. Hence, it is difficult to place the results of this study in the larger realm. It is also necessary to understand how exactly CD47/SIRP-α and CD200/CD200R cause inflammation.

What do the results mean for you?

Reduced levels of CD47/SIRP-α and CD200 in tissue from patients with FCD IIb and TSC may contribute to inflammation and subsequent seizures. Studying this in greater detail and developing therapies to increase their levels may be beneficial in FCD IIb and TSC.

This summary was written by Sloka Iyengar, PhD, a neuroscientist and science writer based in New York (May 2016).

Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis

Helen S. Bateup, Caroline A. Johnson, Cassandra L. Denefrio, Jessica L. Saulnier, Karl Kornacker, Bernardo L. Sabatini
Neuron. 2013 May 8;78(3):510-22.
DOI: 10.1016/j.neuron.2013.03.017

What is the topic?

Tuberous sclerosis complex (TSC) is a genetic disorder that is caused by mutation in genes called TSC1and TSC2 – this causes over-activation of a protein complex called mammalian target of rapamycin complex 1 (mTORC1). TSC is associated with numerous complications –the neurological ones being developmental disorders and seizures.

Neuronal (nervous system) networks are made up of neurons (nerve cells) that are connected to each other via synapses (connections between nerve cells).  One of the defining properties of the brain is its capacity to undergo activity-dependent alterations in synapses. This capacity of the brain to ‘rewire’ (also known as ‘plasticity’) is what helps us form new memories, retain old ones and regain functionality after an injury such as a stroke. Activity-dependent plasticity of neuronal networks depends on a fine balance between excitation and inhibition, and aberrations in this balance can cause neurological disorders.

What did the researchers hope to learn?

TSC is associated with seizures and neurodevelopment disorders; the authors wanted to find out whether alterations that are seen in TSC are sufficient to cause hyperexcitability in experimental subjects. The reason for examining this is that if we know the mechanisms that can cause seizures in TSC, we can potentially target them to stop seizures.

Who was studied?

Two approaches were taken in this study – in vitro (meaning ‘outside of the living organism’) and in vivo(meaning ‘inside the living organism’). The authors studied a part of the brain called the hippocampus because of its importance in seizure generation and propagation. The in vitro approach consisted of hippocampal neurons that were removed from the brain of transgenic (genetically modified) mice with reduced levels of the protein TSC1. In the in vivo approach, scientists studied the seizure properties of experimental mice with reduced levels of TSC1.

How was the study conducted?

The authors used the dissociated hippocampal cultures to study electrical properties of neurons. Drugs that cause seizures in the lab are called chemoconvulsants – one of them is kainic acid (KA). KA was given to mice that had reduced TSC1 to see how these mice with mutated TSC respond to seizures.

What did the researchers find?

Neuronal hyperexcitabity or the phenomenon in which neurons are excessively excitable is thought to underlie seizure generation and propagation. The in vitro studies show that when levels of the protein TSC1 were decreased, there was a greater level of hyperexcitability. In experimental mice, administration of KA in animals with lower TSC exhibited more seizures. The reason behind this was that there was an imbalance between excitation and inhibition.

What were the limitations of the study?

This study was done in experimental animals, and despite the interesting and exciting results, more studies need to be performed in tissue from human subjects with TSC to confirm that the same biological mechanisms are at play.

What do the results mean for you?

Up until now, it was known that mutations in TSC genes interact with mTORC1 to eventually cause seizures and developmental disorders. This study takes this a step further because it shows the exact mechanism by which TSC can cause seizures and developmental delay i.e.by altering the excitation / inhibition balance.

This summary was written by Sloka Iyengar, PhD, epilepsy researcher at the Northeast Regional Epilepsy Group studying aspects of brain tumor-related epilepsy, mood disorders in epilepsy and special issues in women with epilepsy.  She is also a science writer and contributes regularly to numerous websites to make neuroscience research more accessible to non-scientists. (December 2014).

Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex*

Jóźwiak S, Kotulska K, Domańska-Pakieła D, Lojszczyk B, Syczewska M, Chmielewski D, Dunin-Wąsowicz D, Kmieć T, Szymkiewicz-Dangel J, Kornacka M, Kawalec W, Kuczyński D, Borkowska J, Tomaszek K, Jurkiewicz E, Respondek-Liberska M.

Eur J Paediatr Neurol. 2011 Sep;15(5):424-31. Epub 2011 Apr 19.

doi: 10.1016/j.ejpn.2011.03.010.

What is the topic?  Epilepsy appears in 70-80% of patients with TSC (tuberous sclerosis complex), most commonly beginning in the first year of age. Early onset of epilepsy (especially infantile spasms) is associated with seizures that are multi-drug resistant as well as mental retardation in more than 80% of patients. The authors state that prior to the appearance of clinical seizures in infants the EEG (electroencephalogram, a test to measure electrical activity of the brain) will show abnormal activity.  This would allow doctors to identify infants with high risk of epilepsy and begin treatment to prevent the seizures from happening.

What did the researchers hope to learn?   The authors wanted to find out if giving antiepileptic medication to infants with abnormal EEG results, before the onset of clinical seizures, might lower the incidence of drug-resistant epilepsy and mental retardation.

Who was studied?  Forty-five infants with early diagnosis of TSC were included in the study. They were divided in two groups: Standard (31 patients) and Preventative (14 patients). In the Standard group the antiepileptic treatment was started early, but after seizures were seen. In the Preventative group medication was started when the EEG was abnormal, but before seizures were seen. Children were followed until the end of the 24^th month of age. In both groups of children, the antiepileptic drug of first choice was vigabatrin.

What did the researchers find?   At 24 months of age mental retardation was significantly more frequent and severe in Standard vs. Preventative group.  In the Standard group, 48% were considered to have mental retardation (with an average IQ score of 68.7), while only 14% of the Preventative group demonstrated mental retardation (with an average IQ score of 92.3). Mental retardation was observed only in patients with epilepsy. The Preventative group had more seizure-free patients (93% vs 35%), less drug-resistant epilepsy (7% vs 42%), and fewer patients requiring multiple epilepsy drugs (21% vs 55%) than the Standard group.

What were the limitations of the study?   The study did not involve a large number of patients.  The study did not include long term follow up of subjects to determine if the positive effects were lasting or if there were any negative consequences later in life.  More research with larger numbers of patients, longer follow up, and more data on other variables that could influence development of epilepsy and mental retardation might be needed to change the way physicians care for newly diagnosed TSC infants to include EEG testing on a regular basis.

What do the results mean for you?   In the past, recommendations for EEG testing were to wait for clinical signs of seizures before performing an EEG.  The recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Group now advise that baseline EEG recordings be obtained at the time of diagnosis, however this article goes a step farther in suggesting that TSC infants should continue to be given routine EEG screening in order to identify the children at highest risk for damaging early seizures such as infantile spasms.  The authors recommend that treatment should begin before clinical signs of epilepsy, when EEGs show abnormal activity that is likely to lead to seizures.  They state that vigabatrin should be the first line of treatment and should be continued until the end of the second year of age. However, these changes may not be seen in the doctors’ offices until enough data is published to convince doctors and parents that it is safe to give these medications preventatively, and to convince insurance companies or governmental healthcare providers to pay for the additional testing and medication when seizures have not yet been seen.

This summary was written by Cristy Wade, MS, parent of child with TSC, and consumer reviewer for the Tuberous Sclerosis Complex Research Program (July 2014).

Everolimus treatment of refractory epilepsy in tuberous sclerosis complex

Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN.

Ann Neurol 74(5):679-687, 2013

DOI: 0.1002/ana.23960

What is the topic?  Epilepsy is a common manifestation of Tuberous Sclerosis Complex (TSC).  At least 1/3 of individuals with TSC and epilepsy do not respond to treatment with conventional antiepileptic drug (AED) therapies or surgery.  Behavioral and learning problems are more common in this group. TSC is caused by abnormalities in two genes called TSC1 and TSC2, and abnormalities in these genes alter regulation of a protein complex known as mammalian target of rapamycin complex 1 (mTORC1). Past studies have found that inhibiting the mTORC1 complex was beneficial for other manifestations of TSC.

What did the researchers hope to learn? This study was done to see whether inhibiting the mammalian target of rapamycin complex 1 (mTORC1) complex using everolimus would reduce seizures in individuals with TSC.

Who was studied?   This was a study conducted at Cincinnati Children’s Hospital and Texas Children’s Hospital (Houston) with twenty participants between 2-21 years old with a confirmed diagnosis of TSC and epilepsy who did not respond to standard treatment.

How was the study conducted?   After the baseline observation period, everolimus was administered with the dose titrated (adjusted) to a target drug level over a 4-week period.  Once the adequate dose was determined, study participants were administered that dose for 8 weeks.  During the treatment phase, blood tests, quality of life and behavioral assessments, and video-EEG monitoring (vEEG) were also done.

What did the researchers find?   More than half of the study participants (12 out of 20) reported a reduction in seizure frequency with everolimus – this was observed both by video-EEG recording and by parental reports. Parents reported an overall improvement in quality of life, and the behavioral assessment showed everolimus treatment to have a greater impact on reducing negative behaviors (such as conduct problem, anxiety, self-injurious), than increasing positive behaviors (such as compliant/calm). There were reports of treatment-related adverse effects, although they were mild to moderate in severity.   Upper respiratory infection and stomatitis (mouth sores) were the most common.

What were the limitations of the study? The sample size (number of individuals participating in a study) was relatively small.   The observed benefits of the study may have been due to the unintentional selection of individuals who had as yet an undetermined advantage to respond more favorably to everolimus.    Also the reported improvement in seizure frequency, quality of life, and behavior may have been influenced by knowing the participants were receiving everolimus instead of a placebo (a pill with no treatment value). However, the reduction in seizure frequency was also observed on vEEG which correlates to the reported improvements by the parents.

What do the results mean for you? Epilepsy (even without TSC) is a neurological disorder that is often associated with significant burdens on the quality of life of the affected individual and their family.   The results of this study suggest everolimus may be a safe and effective treatment option for some individuals who do not respond to treatment with the usual AED therapies. However, more studies need to be done with larger number of participants to confirm the observed benefits from this small study.