Cortical Dysplasia

Cortical dysplasia is a genetic brain condition where cells in the outer layer of the brain don’t form properly before birth. It is one of the most common causes of epilepsy in children and a frequent cause of seizures that don’t respond well to typical medications. While challenging to treat, surgery and other therapies can offer hope for seizure control.

Table of contents

• What is cortical dysplasia?
• Types of cortical dysplasia
• Parts of the brain affected
• What causes cortical dysplasia?
• Symptoms
• How is it diagnosed?
• Treatment options
• Outlook

focal cortical dysplasia, FCD, neocortical dysplasia

What is cortical dysplasia?

Cortical dysplasia is a rare condition that affects the brain’s development before a child is born^[1]. The word “dysplasia” refers to abnormal or unusual cells in the body. In this condition, groups of cells in the cerebral cortex (the outermost layer of the brain) didn’t form properly during development in the womb^[1].

This condition is a congenital abnormality, meaning it is present from birth. It occurs when the top layer of the brain does not form properly^[2]. Healthcare providers sometimes call it focal cortical dysplasia or FCD because it is limited to a specific area in any part of the brain^[7].

Cortical dysplasia is one of the most common causes of epilepsy. It accounts for nearly half of all cases of difficult-to-treat epilepsy in both children and adults^[4]. In fact, it is the most common reason children need epilepsy surgery^[5].

• Cerebral cortex (outer layer of the brain)
• Temporal lobe
• Frontal lobe
• Gray matter
• White matter

Types of cortical dysplasia

Healthcare providers classify cortical dysplasia into three main types based on how the abnormal cells form in the brain and which areas are affected^[1].

Type 1 (Type I) involves abnormal cells that formed incorrectly in the cortex or made brain cells organize in ways they shouldn’t^[1]. The cortex is normally made of six horizontal layers of cells, but in Type I, it is not properly organized. The cells may be arranged in vertical columns or the six layers may be lost^[3]. This type can affect any lobe but is most common in the temporal lobe or frontal lobe^[1]. Type I is hard to see on a brain scan, and patients often don’t start having seizures until they are adults^[2].

Type 2 (Type II) is more severe than Type 1. In this type, cells in the cerebral cortex are too big or look different than they should^[1]. Like Type I, neurons are abnormally organized, but there may also be large neurons called balloon cells present^[3]. Type II is seen more often in children and commonly affects the frontal and temporal lobes^[1]. Changes are more easily seen on brain imaging tests^[3].

Type 3 (Type III) happens when you have either Type 1 or Type 2 cortical dysplasia along with other abnormalities in the brain^[1]. These can include brain tumors, unusual blood vessels, brain scarring (such as in the hippocampus), or damage from brain injury early in life^[2][3]. It can affect any lobe depending on where the tumor formed or the injury damaged the brain^[1].

Each type may be further divided into subgroups. For example, Type I has subtypes a and b, Type II has subtypes a and b, and Type III has subtypes a, b, c, and d based on specific features seen under a microscope^[3].

Parts of the brain affected

Cortical dysplasia affects the cerebral cortex, which is the outermost layer of the brain. This part of the brain controls your body’s movement, your thoughts, speech, memory, intelligence, and personality^[1].

Different types of cortical dysplasia tend to affect different regions. Type 1 most commonly involves the temporal lobe of the brain^[2]. Type 2 normally involves both the temporal and frontal lobes^[2]. Type 3 can affect any part of the brain depending on where other damage has occurred^[1].

The condition affects both the gray matter (the cortex itself) and sometimes the white matter underneath. Brain imaging tests can show changes in these areas, such as blurring between the gray and white matter or bright streaks extending from the gray matter into the white matter^[3][4].

What causes cortical dysplasia?

Cortical dysplasia is a genetic condition. A genetic change caused the brain to form differently than usual during development before birth^[1]. This often occurs before the child is born and is not a result of anything the mother took during pregnancy^[2].

Researchers cannot say for certain which genetic change causes it, as they are still studying potential causes^[1]. However, some experts think that a genetic change affecting the MTOR pathway genes causes cortical dysplasia type 2. This gene produces a protein that helps cells form and grow, especially in the brain. A genetic change that alters the MTOR genes may cause it to make different or incorrect kinds of cells^[1].

Recent studies have shown that cortical dysplasia types 2a and 2b result from changes in genes that encode components of the mammalian target of rapamycin (mTOR) pathway^[7]. Gene mutations associated with these types include MTOR, PI3KCA, AKT3, and DEPDC5^[7]. Brain-only mutations in genes TSC1 and TSC2 have also been found in individuals with focal cortical dysplasia type II^[14].

These mutations lead to enhanced mTOR pathway signaling at critical periods in brain development^[7]. The mTOR pathway controls a number of functions in the brain including establishment of cell size, cell movement, and development^[7].

There are both genetic and acquired factors involved in the development of cortical dysplasia^[5]. Some causes may also be due to brain injury^[2].

Symptoms

Seizures are the most common symptom of cortical dysplasia^[1][2]. The abnormally formed cells in the brain do not work as they should. Instead, they may send abnormal electrical signals that cause seizures^[3].

There are several types of seizures that can occur with cortical dysplasia:

• Focal seizures start in one side of the brain and don’t spread to the other side. You might twitch, jerk, or shake, but not everyone does^[1].
• Tonic-clonic (grand mal) seizures spread to affect both sides of the brain. They cause uncontrolled shaking or movement on both sides of the body^[1].
• Infantile spasms are a special type of seizure that only affects children younger than 1. Babies having an infantile spasm quickly extend then flex their arms, legs, and neck^[1].

Seizures may start at any point in life. Some people first have them as infants or children, but it’s possible you won’t experience the first seizure until adulthood^[1]. Seizures in focal cortical dysplasia appear in the first five years of life for about two thirds of people. Most of the rest will have started having seizures by the time they turn 16. Initial onset in adults is much rarer^[22].

Other symptoms you may experience include:

• Trouble concentrating^[1]
• Trouble learning new concepts or ideas^[1]
• Problems with the ability to learn new things^[2]
• Muscle weakness on one side of the body (called hemiparesis)^[1]

Cortical dysplasia can also affect the brain’s physical structure, but only a healthcare provider will be able to see these symptoms using an MRI. They’ll identify changes in the brain’s cortex (gray matter)^[1].

How is it diagnosed?

A healthcare provider will diagnose cortical dysplasia with imaging tests^[1]. This kind of epilepsy can sometimes be challenging to diagnose. For example, a cortical dysplasia MRI scan may not always be able to identify the cells which are causing the seizures^[22].

Your provider will ask you to tell them which kinds of symptoms you’ve noticed and when they first happened^[1]. Doctors use a number of methods for diagnosing focal cortical dysplasia, including:

Brain MRI (Magnetic Resonance Imaging) is the main imaging test used. Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias^[4]. The most common findings on MRI imaging include focal cortical thickening or thinning, areas of focal brain shrinkage, blurring of the boundary between gray and white matter, and increased signal on certain image types in the gray and outer white matter often tapering toward the fluid-filled spaces in the brain^[4].

EEG (Electroencephalogram) is a device worn on the head that measures electrical activity in your brain^[22]. This test helps identify where seizures are starting.

FDG-PET scan can demonstrate areas of reduced metabolism affected by the dysplasia^[5]. Advanced imaging techniques use the fusion of a high resolution MRI with an FDG-PET study to detect these subtle changes^[5].

Magnetoencephalography (MEG) is a non-invasive technique that can localize the abnormal electrical activity to find and assess the size of the affected area^[5].

A detailed medical history of when you began having seizures and the types of seizures you had is important^[22]. Other symptoms of a dysplasia, including language learning delays and visual problems, may also help with diagnosis^[22].

The only way to diagnose a type of focal cortical dysplasia for certain is to look at tissue under a microscope after surgery^[3]. Tests for genetic changes in the DNA of the tissue may also be used to help clarify the diagnosis^[3].

Treatment options

Treatment is focused on controlling the seizures^[2]. No specific treatment is required for cortical dysplasia itself, and all treatment is aimed at the resulting symptoms, which are typically seizures^[7].

Medications

Antiepileptic drugs (AEDs) have been widely used in the treatment of cortical dysplasia^[9]. When cortical dysplasia causes epilepsy, seizure medications (anticonvulsants) are a first line treatment^[7]. Your doctor may start with medicine to try to control the seizures^[2].

However, cortical dysplasia is one of the types of epilepsy which is least responsive to treatment by medication. This is called refractory epilepsy or drug-resistant epilepsy. Around 4 in 5 people with focal cortical dysplasia find that drugs do not control their seizures^[22]. Evidence to suggest specific effects of medications on treatment of cortical dysplasia remains to be established^[9].

Ketogenic diet

A special diet called a ketogenic diet may be tried to help control the seizures^[2][10]. This diet has been shown to modify disease progression and is particularly important in children with cortical dysplasia^[9].

Surgery

Brain surgery may be another treatment if the patient still has seizures after trying different medicines^[2]. If anticonvulsants fail to control seizure activity, neurosurgery may be an option to remove or disconnect the abnormal cells from the rest of the brain^[7].

A complete removal of the area causing seizures (called the epileptogenic zone) is required for seizure-free life^[4]. Surgery is a viable treatment option for appropriate candidates^[7]. Studies have shown that removing the part of the brain which is causing the seizures can lead to seizure freedom for as much as 67% of people^[14].

Neurosurgery can range from removing an entire hemisphere (hemispherectomy), a small area (lesionectomy), or multiple cuts to try to disconnect the abnormal tissue from the rest of the brain (multiple subpial transsections)^[7]. Risks for surgery include infection, seizures, and decreased motor function^[2].

However, sometimes the affected area of the brain can be larger than the abnormality revealed by the MRI, which can cause poor outcomes if surgery is based on MRI data alone^[5]. In type I cortical dysplasia, MR imaging is often normal, and in both types the area seen on MRI may be smaller than the seizure-generating region^[4]. The abnormalities may also involve vital parts of the brain where surgery will not be an option^[4].

Vagus nerve stimulation (VNS)

Another treatment option may be a vagal nerve stimulator (VNS). This may be considered if brain surgery is not an option^[2][10]. For widespread dysplasias, VNS has been shown to produce responder rates of greater than 50%^[9]. Risks for having VNS surgery are infection and continued seizures^[2].

mTOR inhibitors

Research has provided evidence that mTOR inhibitors, such as rapamycin or everolimus, are promising anti-epileptic drugs for the treatment of focal cortical dysplasia^[9]. In fact, everolimus is currently under phase II clinical trial for the treatment of focal cortical dysplasia^[14].

Other therapies

Physical therapy should be considered for infants and children with muscle weakness. Educational therapy is often prescribed for those with developmental delays^[7].

You should call your doctor if seizures continue or get worse, if there are any side effects to the medicine, or if you have any questions or concerns^[2].

Outlook

Focal cortical dysplasia is responsible for nearly half of intractable epilepsy cases in children and adults, and at the same time it is characterized by quite good treatment outcome^[4]. The condition does not grow or spread to other parts of the brain over time^[3].

Many children with cortical dysplasia require invasive brain surgery as treatment because the condition is often drug-resistant epilepsy. However, even in cases where surgery is performed, up to 40% of these children may still have seizures^[14]. Risks for not doing surgery include increased seizures, loss of skills, and poor quality of life^[2].

By identifying genes associated with focal cortical dysplasia as well as creating new ways of studying the genetic mechanisms behind the disorder, researchers have made progress towards the creation of novel, non-surgical targets at which to aim treatments for this form of drug-resistant childhood epilepsy^[14].

With advances in both genetics and neuroimaging, we may develop a better understanding of patients with drug-resistant epilepsy, which will help us to provide more successful treatment in the future^[4]. Although living with focal cortical dysplasia can be challenging, getting it diagnosed early and exploring treatment options means you might be able to gain greater control over your seizures^[22].