What Is Hemimegalencephaly?

Introduction

Hemimegalencephaly is a rare brain disorder that is caused by a malformation during fetal development that affects one of the cerebral hemispheres.¹ This enlarged hemisphere will cause symptoms such as seizures and motor and cognitive deficits.² 

This article will explain the causes, symptoms and diagnosis of Hemimegalencephaly.

What is hemimegalencephaly?

Hemimegalencephaly (HME) is a rare cortical malformation characterised by enlargement of all or a part of a cerebral hemisphere. It is also often accompanied by cortical dysplasia, white matter hypertrophy and dilated lateral ventricle.³ These variations in the size and structure of the brain tissue will lead to frequent seizures. HME is rare, and its occurrence varies between 1 to 3 cases per 1000 children with epilepsy.⁴ HME is often associated with other disorders such as Klippel-Trenaunay syndrome, Proteus syndrome, linear sebaceous nevus syndrome, neurofibromatosis, Sturge-Weber syndrome and tuberous sclerosis.⁵

Causes and development of HME 

Hemimegalencephaly is characterised by the enlargement of one of the hemispheres, and this enlargement is due to a defect in the PI3K-Akt-mechanistic target of the rapamycin (mTOR) pathway. In fact, this pathway coordinates cell growth during embryonic development. Hyperactivation of this mTOR pathway leads to the formation of larger neurons, more dendrites, glial cells and faster apoptosis of neurons in the ventricular layer. 

This abundance of abnormally large neurons and glial cells then migrates from the ventricular layer to the cortex causing the overgrowth of one hemisphere. The main genes involved in the mTOR pathway are AKT3, PIK3CA, MTOR, and DEPDC. If they undergo a mutation, they are the ones that cause Hemimegalencephaly.  The reason behind the mutation of these genes has not yet been fully understood, but what we do know is that it is caused by a mutation in the genetic material (DNA).^5,6

Symptoms of HME 

The most common symptoms are seizures, which are present in more than 80% of affected patients. Other frequent symptoms are abnormal skull morphology, asymmetry of the cranial bones, malformation of areas of the neocortex, abnormal cortical layering, enlarged gyri (wrinkle-like structure in the brain assisting in cognitive functions), augmentation in the ventricular system and abnormal grey-white matter differentiation.^5,7

There are three types of seizures observed in patients with HME: 

• Focal motor seizures: characterised by starting with a motor sign such as a muscle twitching
• Atonic seizures: a motor seizure where there's a sudden decrease in muscle strength, lasting about 1 to 2 seconds, involving the head, body, jaw, or limbs, without a previous noticeable myoclonic or tonic event
• Status epilepticus: a prolonged seizure causing neural death and changes in neuronal networks.⁵

It is frequent for patients to have psychomotor retardation, which are challenges in speech and movement. This is caused by abnormal brain architecture and disruption of neuronal networks, which then impedes cognitive abilities, affecting learning, movement and problem-solving.⁵

Diagnosis

A suspicion of hemimegalencephaly can be determined by frequent seizures, but the definitive diagnosis can be made through different clinical tests. 

Hemimegalencephaly is officially diagnosed using brain imaging techniques such as magnetic resonance imaging (MRI),  computed tomography (CT) scans and Electroencephalograms (EEG).¹ Two types of asymmetrical EEG can be observed in an affected patient. In some newborn babies, the affected hemisphere will show recurrent epileptiform discharges. Epileptiforms are abnormal electrical discharges indicative of excitability in the cortex. In other newborn babies, there is a pattern in the EEG background known as suppression burst.^10,5 This pattern is formed of alternation between high-voltage waves and suppressed waves indicating signs of seizures.⁵

Through the MRI or CT scan, a physician will be able to diagnose HME if they see an enlarged ventricle or enlarged gyri and if they can see signs of premature myelination of white matter. Myelination is the process of formation of a myelin substance sleeve around neurons to improve their efficiency. In a normal infant, the white matter should not be myelinated. If there is a sign of premature or abnormal myelination, it is an indicator of altered neural connectivity, potentially contributing to symptoms such as seizures and developmental challenges.¹¹

The diagnosis can also be made through an ultrasound during pregnancy. After 26 weeks of gestation, we can usually see the first signs of HME. If the child presents with cerebral and hemispherical overgrowth, leading to a change in the central alignment of the fetal head, then we can make an in-utero diagnosis leading to better neonatal care and eventual C-section if the circumference of the head is larger than 40 cm.¹²

Treatment

The seizures linked with hemimegalencephaly are often resistant to anti‐epileptic drugs (AEDs), which is why the most common method of treatment is hemispherotomy. A “functional hemispherectomy” is a surgical procedure where the nerve and tissues in between the two hemispheres are cut, leaving the enlarged hemisphere in the cortex. A full hemispherotomy involves separating the hemispheres and removing the abnormal one from the cortex. Undergoing a hemispherotomy has led to patients with less or no seizures, shorter duration of epilepsy and absence of malformation in the non-affected hemisphere).^1,7 The documented rates of being free from seizures in groups of patients who underwent hemispherotomy vary between 50% and 90%7. However, even though more than half of the patients are seizure-free after a hemispherotomy, results show that 70%-92% of operated individuals still have intellectual disabilities.⁷

Research and advancements

In recent years, a new, less invasive surgery called Endovascular embolic hemispherectomy was tested on infants, resulting in a significant reduction in seizures. This surgery had the advantage that it could done to an infant under 8 weeks because it has a lower mortality and complication rate than a hemispherectomy.  Being able to do a surgical intervention faster can help avoid having to leave the baby without any treatment for their seizures during the first 8 weeks of their lives. An endovascular embolic hemispherectomy is accomplished by embolisation (blocking) of the cerebral blood supply of the affected hemisphere, resulting in the cessation of seizures.^13,14,15

Another treatment was discovered recently, the use of mTOR inhibitors to reduce an infant’s rate of seizures before they are big enough to undergo surgery. As we know, HME is due to a malfunction of the mTOR pathway by releasing an mTOR inhibitor; the seizures were able to decrease by 50% in 1 week.¹⁶

Long-term outlook

When considering the different long-term outlooks for patients with HME, it is important to know that it is highly variable, with some patients achieving seizure-free and better cognitive results while others still suffer recurrent seizures and have neurological disabilities. However, there is a possibility for specialised therapy for patients with HME, which has proven to improve patients’ lives. It is also advised for the parents of affected children to join support groups in order to gain financial aid and information and share experiences with other families.⁵

FAQs

• Is hemimegalencephaly hereditary? No, the malformation is not inherited.¹⁸
• Is a certain sex more likely to have hemimegalencephaly? No, the disease shows no sex preference.^,7
• My child has hemimegalencephaly, what can I do? Consulting with medical professionals who specialise in neurology and developmental disorders is essential for accurate diagnosis, treatment planning, and support. Speech therapy, feeding therapy, and occupational therapy might be good options to invest in in order to help with the child’s development.¹⁹
• When do seizures normally start? The seizures usually start between the first day of life up until 2 years and 6 months.
• Is there a cure for Hemimegalencephaly? No, there is no cure for HME but only alleviation of symptoms such as seizures.

Summary

hemimegalencephaly (HME) is a rare brain disorder stemming from fetal development malformation that impacts one hemisphere. This condition is characterized by an abnormally enlarged and dysplastic hemisphere, giving rise to symptoms like seizures, motor deficits, and cognitive challenges. HME's complexity is rooted in cortical malformation, often accompanied by cortical dysplasia, white matter hypertrophy, and ventricular dilation. The variations in brain tissue size and structure lead to the frequent occurrence of seizures, found in over 80% of patients, are a common symptom of HME, along with abnormal skull morphology and malformation of neocortex areas. The condition frequently causes psychomotor retardation, contributing to speech and movement challenges due to abnormal brain architecture. Diagnosing HME involves clinical tests, brain imaging (MRI, CT scans), and EEG recordings. The treatment landscape for HME is challenging, with seizures often unresponsive to anti-epileptic drugs. 

Hemispherectomy is a common surgical treatment method. Despite its success in reducing seizures (50% to 90% seizure freedom rates), cognitive disabilities remain a concern in a significant portion of cases. In conclusion, understanding the intricacies of HME is essential for accurate diagnosis and effective treatment in order to provide specialized care for those affected by this complex neurological disorder.

If your child is having frequent seizures, seek medical attention to get an electroencephalogram test in order to know if they are affected by HME. The earlier a child is diagnosed, the faster they can get treatment, resulting in less damage to their cognitive abilities.16 In most individuals with HME, the onset of seizures occurs within the first day of life, up to 2 years and 6 months, so this is the time parents and healthcare professionals should be the most attentive to potential symptoms.¹⁷