TSC Research Article Summaries: Brain

Interdependence of clinical factors predicting cognition in children with tuberous sclerosis complex

Author(s): I. E. Overwater, B. J. H. Verhaar, H. F.Lingsma, G. C. B. Bindels-de Heus, A. M. W. van den Ouweland, M. Nellist, L. W. ten Hoopen, Y. Elgersma, H. A. Moll, M. C. Y. de Wit;  Journal of Neurology 2017 Jan;264(1):161-167; DOI: 10.1007/s00415-016-8335-5

What is the topic?

TSC can be associated with delays in cognitive development. However, this is can be quite variable, leading to lack of information on the part of the physicians to counsel parents. If there were predictors that correlated with the child’s intellectual capability, it would help parents and physicians to develop an individualized educational plan for the child.

What did the researchers hope to learn?

The researchers wanted to learn if there were any factors in early life that correlated with cognitive development in subjects with TSC.

Who was studied?

The study was done in 102 patients with TSC at a TSC center

How was the study conducted?

This was a retrospective follow-up clinical database study, which means that the data was collected, and the researchers went back and analyzed it later. Patients were treated at a TSC center. The researchers collected data from the first two years of patients’ lives. The data that was studied was genetic mutation data, information about epilepsy and seizures, and motor development. They wanted to see if any of these factors correlated with cognitive development.

What did the researchers find?

The factor that most reliably correlated with a decrease in cognitive functioning was the age when seizures started. Hence, if the child was older when seizures started, his (or her) intellectual equivalent was higher.

What were the limitations of the study?

This study did have a few limitations – it is possible that the sample of patients studied here were more severely affected, because they were at a university hospital. This would mean that the results of this study are not universally true for all patients with TSC. The bigger question that this study raises, however, is why the age of onset of seizures is an important predictor of intellectual capability in patients with TSC.

What do the results mean for you?

Cognitive development in TSC is variable and difficult to predict. It would be useful if parents, and physicians have guidance as to the trajectory of the child’s cognitive capabilities. This study provides clues into this important question, and hopefully, can be used to develop individualized educational programs children with TSC.

This summary was written by Sloka Iyengar, PhD, a neuroscientist, science writer, and healthcare consultant based in New York (January 2017).

Subependymal Giant Cell Astrocytoma: Diagnosis, Screening, and Treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012

Authors: Jonathan Roth, MD,E. Steve Roach, MD, Ute Bartels, MD, Sergiusz Jóźwiak, MD, Mary Kay Koenig, MD, Howard L. Weiner, MD, David N. Franz, MD, Henry Z. Wang, MD
Pediatric Neurology Volume 49, Issue 6, Pages 439–444, December 2013.

What is the topic?

Subependymal giant cell astrocytoma (SEGA) is a type of brain tumor that occurs in 10% to 20% of tuberous sclerosis complex (TSC) patients. SEGA very rarely appear in TSC patients older than age 25.  SEGA usually grow slowly, but they can cause serious health problems and even death by blocking the flow of fluid within the brain. Therefore, SEGA often require some sort of medical intervention.  This article summarizes the latest recommendations by a panel of top TSC experts for managing SEGA.

What types of growths can be found in the TSC brain?

Patients with TSC can have cortical tubers (80 – 100%), subependymal nodules (SEN) (90% +), and SEGA (10 – 20%).

Cortical tubers are collections of abnormal cells found in the brain tissue.  They tend to remain stable throughout life and are thought to be associated with seizures and autism.

“Subependymal” describes the layer of cells lining the ventricles, which are fluid-filled spaces in the brain. SEN are small growths that protrude into the ventricles.  SEGA are also growths that protrude into the ventricles, however rather than remaining stable like SEN, they grow.  According to this article, scientists are not sure whether some SEN can turn into SEGA, or if they arise separately.  Some tests may help with telling them apart, such as contrast dye on MRI, but the most important difference between them is evidence of growth (SEGA grow, SEN do not).

SEGA is considered a subependymal lesion that is more than 1 cm in any direction, or a subependymal lesion that has shown continued growth on consecutive imaging (such as MRI).

Why are we concerned about SEGA?

SEGA are considered a type of benign tumor, meaning they are not cancerous (do not spread to other parts of the body).  However, they are a major cause of harm and death in TSC patients.  As they grow, they can block the flow of fluid in the brain.  This leads to a condition called hydrocephalus (“water on the brain”).  Symptoms may include headaches, changes in vision (blurred or double vision, loss of vision), nausea or vomiting, clumsiness or inability to walk, behavioral changes, or increased seizures.  Hydrocephalus caused by the SEGA can be life threatening.

What monitoring is needed?

Brain imaging, preferably MRI (with and without contrast), should be performed every 1 to 3 years until the age of 25 years.  New SEGA very rarely arise in individuals over age 25, but existing SEGA may still need to be monitored beyond that age.  Symptoms concerning for hydrocephalus should trigger an earlier scan, and a growing SEGA should prompt more frequent scans.

What are the treatments?

While previously surgery was the only treatment option available for SEGA, recent trials have shown mTOR inhibitors to be very effective in shrinking the tumors.  Examples of mTOR inhibitors are sirolimus (also known as rapamycin and marketed in the U.S. as Rapamune®), and everolimus (marketed in the U.S. as Afinitor®).  However, mTOR inhibitors do not work for everyone, and the tumors often grow back if the medication is stopped.  It is not yet known what the long-term effects of taking such medication for a lifetime might be.  So, there is not one clear choice for SEGA treatment at this time.  For some patients, medication is given to shrink the tumor before it is surgically removed. Several factors have to be weighed in making the decision between medication and surgery:

• Clinical condition – If a SEGA is found that is already causing symptoms of hydrocephalus, or is hemorrhaging, surgery will probably be required.  However, if the SEGA is not yet causing problems then all options might be considered.
• Size, number, location – If a SEGA is invading neighboring brain tissue, then surgery is more dangerous.  Larger tumors may also be more dangerous to remove because of bleeding risks and having to retract more brain tissue.  If the tumor tissue cannot be completely removed, it is at high risk for growing back.  It is also difficult to safely remove multiple tumors that could be on each side of the brain.
• Experience – Some clinics and physicians are more experienced with one treatment over the other, and it could be safer for a patient to be treated in the manner the clinical staff is most skilled.
• Other TSC symptoms – Some conditions associated with TSC make surgery less safe, such as heart arrhythmias or kidney or lung problems.  Some TSC conditions might also benefit from treatment with an mTOR inhibitor, such as if the patient also has growing kidney tumors (angiomyolipomas) or facial tumors (angiofibromas).
• Patient/parent preference – Since one treatment is not clearly better than the other in all situations, families should understand the pros and cons of both types to make an informed choice.

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).

MR-guided stereotactic laser ablation of epileptogenic foci in children

Author(s): Daniel J. Curry, Ashok Gowda, Roger J. McNichols, Angus A. Wilfong;
Epilepsy & Behavior 24 (2012) 408–414. DOI (of the article): 10.1016/j.yebeh.2012.04.135

What is the topic?

Anti-epileptic drugs (AEDs) are the first line of treatment for epilepsy, but one-thirds of the population does not respond to these drugs. Alternative options for individuals with refractory epilepsy are dietary therapy (e.g. the ketogenic diet) and surgical removal of the epileptic focus (the part of the brain where seizures originate). One of the ways of removing (ablating) the tissue that causes seizures is by magnetic resonance imaging (MRI) – guided ablation of laser interstitial thermal therapy (shortened to ‘MRgLITT’). In this paper, the scientists wanted to test the efficacy of MRgLITT in children that had epilepsy.

What did the researchers hope to learn?

Individuals with epilepsy where two AEDs have failed to provide seizure control are known as ‘refractory’ cases. In this study, the researchers wanted to know whether MRgLITT would be able to provide seizure relief in pediatric patients with refractory epilepsy. Basically, MRgLITT is a way of destroying the epileptic tissue using laser; MRI allows one to see in real-time and with great accuracy the part of the brain being destroyed by the laser. One advantage of this technique is that it is minimally invasive (as compared to resection surgery without laser).

Who was studied?

This retrospective study was performed in 5 children with refractory epilepsy. ‘Retrospective’ means that the technique (MRgLITT) was performed and the efficacy in reducing seizure frequency was studied after the fact.

How was the study conducted?

Since the patients were children, consent was taken from their guardians. Past reports had already given an indication of where the seizures were originating from (this was different for each patient). On the day of the MRgLITT surgery, a flexible probe with laser was inserted into the area that needed to be ablated. After this, the patient was transferred to the MRI area where by a special software; the physician could monitor temperature changes caused by the laser. Special temperature maps in addition to MRI allowed physicians to keep track of what tissue was being destroyed – only the tissue that was generating seizures needs to be destroyed, keeping effect on surrounding healthy tissue minimal. Once the epileptic focus is sufficiently destroyed, the incision that was made to insert the laser probe can be closed. Patients were followed up after MRgLITT to observe whether seizures had reduced in frequency.

What did the researchers find?

Follow-up studies found that all patients were seizure-free after MRgLITT procedure. At least in the first few months that the patients were followed, there were no complications because of the ablation technique either. Previous studies have found usefulness of MRI-guided laser ablation for brain tumors, but this is among the first studies that observed its usefulness in refractory epilepsy.

What were the limitations of the study?

One limitation of the study is the small sample size. However, the results seen are an impetus to perform a bigger study with more patients. Post-operative follow-up was done for a short time (i.e. 13 months); observing the effects of MRI-guided laser ablation years down the line would be quite beneficial.

What do the results mean for you?

A big issue in epilepsy research (and a goal of epilepsy researchers) is to better understand the mechanisms underlying refractory epilepsy, and the possible ways to provide seizure relief in cases where AEDs fail to provide relief. The results of this study suggest that MRI-guided laser ablation may be able to reduce seizures in difficult-to-treat cases.