Hemimegalencephaly

What Causes Hemimegalencephaly?

The cause of HME is not well understood.  HME seems to result from a problem early in brain development and is typically present at birth.  The abnormal growth of one side of the brain is likely caused by an anomaly in the genes that control brain development, but it is unclear what causes the problematic gene changes in the first place.  Some scientists believe that the gene damage results from an injury early in pregnancy that affects fetal development.

Is Hemimegalencephaly Hereditary?

HME itself does not appear to be an inherited condition.  Although genetics probably play a role in the development of the disorder, the specific gene mutations that cause it likely are not inherited.  However, some of the underlying conditions commonly associated with HME are inherited, so there is a potential increased risk for HME based on family history of those disorders. 

The risk of inheriting the underlying disorder varies depending on the disease.  For example, Sotos syndrome is inherited in an autosomal dominant pattern.  This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents.  If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

How Is Hemimegalencephaly Detected?

In some cases, depending on the underlying cause, HME may be diagnosed before birth during ultrasound imaging exams.  However, in many cases, the condition is first apparent when a young infant experiences severe seizures.

How Is Hemimegalencephaly Diagnosed?

HME may be suspected when a young infant experiences seizures.  Doctors will take diagnostic steps to rule out other possible causes for the abnormal growth and identify the underlying cause.  The diagnostic process usually includes:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Imaging scans such as magnetic resonance imaging (MRI) to look for the characteristic malformations of the disorder

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Hemimegalencephaly Treated?

The seizures associated with HME usually do not respond well to anti-seizure medications.  Surgical procedures and therapies to manage complications are the most common courses of treatment.

Surgical Treatments

Surgical intervention, when possible, is the most reliable way to relieve seizures and stop the progression of the disorder.  In most cases where surgery is a viable option, seizures are effectively controlled after the procedure.  Surgery may cause permanent side effects, but the hope is that the normal half of the child’s brain will eventually compensate for the affected half.

Possible surgical interventions include:

• Functional hemispherectomy.  This procedure severs the neurological connections between the brain’s hemispheres.
• Anatomical hemispherectomy.  This procedure removes the affected part of the brain.

Therapies 

Other treatments and therapies aim instead to lessen the impact of symptoms and prevent complications.  Common treatments and therapies include:

• Physical therapy
• Occupational therapy
• Special education

How Does Hemimegalencephaly Progress?

The long-term outlook for children with HME depends on the extent of the brain malformation, the underlying cause of the condition, and the effectiveness of treatment.  Many of the disorders associated with HME produce significant symptoms and complications.  Severe disabilities and death are common when these disorders cause abnormal brain development.  Severe, uncontrolled seizures can lead to substantial developmental problems and may be life-threatening.

How Is Hemimegalencephaly Prevented?

There is no known way to prevent HME.  Parents with a family history of any disorders that cause the condition are advised to consult a genetic counselor to assess their risk if they plan to have a child.

Hemimegalencephaly Caregiver Tips

• Be an advocate for your child.  Learn all you can about macrencephaly so you can understand the challenges your child faces, and be prepared to educate others about what they can do to help and support you and your child.
• Remember that you’re not alone.  Connections with others who are going through the same thing can help.  The Child Neurology Foundation maintains educational resources, access to one-to-one peer networks, and links to support groups.

Some people with HME also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with HME and its underlying conditions:

• Many people with HME also suffer from attention-deficit/hyperactivity disorder (ADHD) or learning disabilities.
• A large percentage of people with HME and seizure disorders suffer from depression or anxiety.
• People with seizure disorders such as those associated with HME are at increased risk of developing some psychotic disorders, such as schizophrenia.
• Autism spectrum disorder is more common in people with HME and seizure disorders.
• Several mental disorders, including interictal dysphoric disorder, interictal behavior syndrome, and psychosis of epilepsy, are only experienced by people with seizure disorders.

Hemimegalencephaly Brain Science

Some scientists believe that hemimegalencephaly may result from a neuronal migration disorder that arises during fetal brain development.  In normal embryonic brain development, nerve cells move from the area where they originate to other regions of the brain in a process called neuronal migration.  In their new locations, the cells differentiate and develop to form specialized brain structures.  However, in hemimegalencephaly, some triggering event(s) may disrupt the process, and the nerve cells don’t move as they should.  As a result, one side of the brain is enlarged and may also show other types of malformation.

Hemimegalencephaly Research

Title: Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery

Stage: Recruiting

Principal investigator: Aria Fallah, MD

University of California, Los Angeles

Los Angeles, CA

Refractory epilepsy, meaning epilepsy that no longer responds to medication, is a common neurosurgical indication in children.  In such cases, surgery is the treatment of choice.  Complete resection of affected brain tissue is associated with the highest probability of seizure freedom.  However, epileptogenic brain tissue is visually identical to normal brain tissue, complicating complete resection.  Modern investigative methods are of limited use.

An important subjective assessment during surgery is that affected brain tissue feels stiffer.  However, there is currently no way to determine this without committing to resecting the affected area.  It is hypothesized that intraoperative use of a tonometer (Diaton) will identify abnormal brain tissue stiffness in the affected brain relative to a normal brain.  This will help identify stiffer brain regions without having to resect them.

The objective is to determine if intra-operative use of a tonometer to measure brain tissue stiffness will offer additional precision in identifying epileptogenic lesions.

In participants with refractory epilepsy, various locations on the cerebral cortex will be identified using standard pre-operative investigations like magnetic resonance imaging (MRI) and positron emission tomography (PET).  These are presumed normal and abnormal brain areas where the tonometer will be used during surgery to measure brain tissue stiffness.  Brain tissue stiffness measurements will then be compared with the results of routine pre-operative and intra-operative tests.  Such comparisons will help determine if, and to what extent, intra-operative brain tissue stiffness measurements correlate with other tests and help identify epileptogenic brain tissue.

Twenty-four participants have already undergone intra-operative brain tonometry.  Results in these participants are encouraging: abnormally high brain tissue stiffness measurements have consistently been identified and significantly associated with abnormal brain tissue.

If the tonometer adequately identifies epileptogenic brain tissue through brain tissue stiffness measurements, it is possible that resection of identified tissue could lead to better postoperative outcomes, lowering seizure recurrences and neurological deficits.

Title: Genetic and Electrophysiologic Study in Focal Drug-resistant Epilepsies (GENEPHY)

Stage: Recruiting

Principal investigator: Georg Dorfmuller, MD

Fondation Ophtalmologique Adolphe de Rothschild

Paris, France

Brain somatic mutations in genes belonging to the mTOR pathway are well recognized in malformations of cortical development, such as focal cortical dysplasia or hemimegalencephaly.  The present study aims to search for brain somatic mutations in paired blood-brain samples from children undergoing epilepsy surgery at the Rothschild Foundation, Paris.  Patients and their parents will be recruited to identify genetic abnormalities both in lymphocytic and cortical DNA.

Title: Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations

Stage: Recruiting

Principal investigator: Julian Martinez, MD, PhD

University of California, Los Angeles

Los Angeles, CA

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by social communication/interaction impairments and restricted/repetitive behaviors.  ASD associated with germline heterozygous PTEN mutations (PTEN ASD) is a genetically defined sub-group that may be one of the more prevalent genetic disorders contributing to ASD (0.5-2%).  The purpose of this research study is to carefully track the phenotypic and molecular characteristics of PTEN ASD and identify biomarkers for intervention studies.

Individuals with PTEN ASD, with macrocephalic ASD without a PTEN mutation (macro-ASD), healthy controls, and individuals with PTEN mutations without ASD (PTEN no-ASD) will be asked to participate in this study if they are 18 months and older.  Both males and females will be invited to participate.  Additionally, to be eligible for study participation, individuals’ primary communicative language must be English.

The study involves three on-site visits over two years.  Study visits will vary in length from about 4 hours to 6 hours.  Study visits involve a physical exam, medical history questions, neuropsychological assessments, and a blood draw done for laboratory studies.  A subset of participants between the ages of 2 and 11 will participate in the study’s EEG portion. In addition, individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.