Hemimegalencephaly

Overview

Hemimegalencephaly is a rare neurological condition characterized by the abnormal enlargement of one cerebral hemisphere of the brain. This congenital malformation is a type of cortical dysplasia, where one half of the brain grows larger than the other and often has abnormal structure and function. Hemimegalencephaly can occur as an isolated condition or as part of a broader syndrome, such as tuberous sclerosis complex or Proteus syndrome. The condition is typically identified in infancy or early childhood due to seizures and developmental delays.

Causes

Hemimegalencephaly is believed to result from somatic mutations in genes involved in brain development, particularly those affecting the PI3K-AKT-mTOR signaling pathway. These mutations occur during early brain formation and lead to overgrowth and disorganization of neural tissue. Unlike inherited genetic disorders, the mutations in hemimegalencephaly are usually mosaic, meaning they affect only a portion of the body or brain. In some cases, the condition may be associated with genetic syndromes such as:

• Tuberous sclerosis complex

• Proteus syndrome

• Linear nevus sebaceous syndrome

However, in many cases, the cause remains isolated and not linked to a broader systemic disorder.

Symptoms

Symptoms of hemimegalencephaly typically appear in infancy or early childhood and can vary in severity. Common signs and symptoms include:

• Seizures: Often severe, frequent, and resistant to medication (intractable epilepsy)

• Developmental delay: Delays in motor skills, speech, and cognitive functions

• Hemiparesis: Weakness or paralysis on one side of the body, usually opposite to the enlarged hemisphere

• Intellectual disability: Ranging from mild to profound

• Macrocephaly: An abnormally large head due to brain overgrowth

• Facial asymmetry or other physical anomalies in syndromic cases

Neurological symptoms typically reflect the dysfunction of the overgrown and malformed hemisphere.

Diagnosis

Diagnosis of hemimegalencephaly involves a combination of clinical evaluation and neuroimaging. Key diagnostic tools include:

• Magnetic Resonance Imaging (MRI): The gold standard for identifying asymmetric brain enlargement, abnormal cortical patterns, and white matter changes

• Electroencephalogram (EEG): Detects abnormal electrical activity in the brain, often with epileptic discharges localized to the affected hemisphere

• Genetic testing: May identify mutations in the mTOR pathway or rule out associated syndromes

• Neurological assessment: To evaluate motor, cognitive, and developmental delays

Early diagnosis is essential for planning effective treatment strategies and managing seizures.

Treatment

Treatment of hemimegalencephaly is symptomatic and focuses primarily on seizure control and supportive therapies. Options include:

• Antiepileptic medications: Used to control seizures, though many cases are resistant to drugs

• Ketogenic diet: May help reduce seizure frequency in some patients

• Surgical intervention: Hemispherectomy or hemispherotomy - removal or disconnection of the affected hemisphere, is considered in severe, drug-resistant epilepsy cases and can lead to significant seizure reduction

• Physical and occupational therapy: To manage motor delays and improve mobility

• Speech and cognitive therapy: To support communication and learning abilities

Multidisciplinary care is essential to address the complex and varied needs of affected children.

Prognosis

The prognosis for individuals with hemimegalencephaly varies depending on the severity of the brain malformation and the success of seizure control. Children with milder forms may have better outcomes, while those with severe cases often face lifelong challenges including intractable epilepsy, intellectual disability, and motor impairment. Surgical treatment can dramatically reduce seizures and improve quality of life, though it may result in permanent motor deficits on the opposite side of the body. With early intervention and comprehensive care, many patients can achieve improvements in developmental milestones and day-to-day functioning.