Introduction

Cortical malformations are various congenital disorders that result from abnormal structural development of the cerebral cortex. Abnormalities usually occur during early foetal development, which includes:

• Neuronal proliferation: where brain cells (neurons) rapidly divide
• Neuronal migration: where neurons move to the correct place during cerebral cortex development
• Cortical organisation: where neurons are organised to create the folds of the cerebral cortex

Cortical malformations can cause early-onset epilepsy, developmental delay, motor dysfunction, and intellectual disability. As a result, diagnosis can be challenging without thorough imaging investigations, as each type of malformation presents with characteristic imaging features.¹

Neuroimaging, such as magnetic resonance imaging (MRI), is commonly used to diagnose, classify and differentiate neurodevelopmental conditions. MRIs provide an image of cortical thickness, gyral patterns, and subcortical architecture, which can reveal whether there are any developmental problems due to abnormal formations. Computed tomography (CT) may also be used, but it is less effective at detecting structural abnormalities.² 

It is essential to recognise the various types of cortical malformations for accurate diagnosis and the application of preventive measures, such as genetic counselling and optimal prenatal care. Recognising the symptoms enables doctors to determine when to order neuroimaging tests for diagnosis, as cortical malformations share symptoms with other neurological conditions.³

Overview of cortical malformations

There are various types of cortical malformations, which result from disruptions in neurogenesis (generation of neurons). These processes include neuronal proliferation, migration and cortical organisation. These disruptions can impact the development of the foetal brain, leading to a cortical malformation.⁴ 

Proliferation disorders occur during the early stages of foetal development and involve the production of neurons and glial cells. Neuronal proliferation occurs between the 5th and 12th weeks of pregnancy. The correct number of neurons is essential for proliferation to occur properly and for the cerebral cortex to function effectively. Examples of proliferation disorders can include microcephaly and hemimegalencephaly.⁵ 

Migration disorders are caused by abnormal movement of neurons from the periventricular germinal matrix (where neurons are made) to the cortical plate (outer layer of the brain during foetal development). Neuronal migration occurs between weeks 12 and 24 of pregnancy. A disruption to migration can lead to an incorrect number of neurons for cortical development, resulting in an abnormal structure and function. Examples of the migration disorders include lissencephaly and heterotopia.⁶ 

Lissencephaly: definition and imaging characteristics

Lissencephaly is characterised by a smooth brain appearance resulting from defective neuronal migration. This typically occurs between the 12th and 24th week of pregnancy.⁷ 

There are two types of Lissencephaly:

1. Type I (Classical Lissencephaly) - the cortex is usually smooth because of the presence of no gyri (folds) or broad, flat gyri. They are structured more thickly; however, the cortex is organised
2. Type II (Cobblestone Lissencephaly) - more disorganised, with the surface being bumpy. It is caused by the over-migration of neurons beyond the pial surface (the outermost surface of the brain). It is typically associated with congenital muscular dystrophies

Etiology

Specific genetic mutations affect neuronal migration. For example, LIS1 (PAFAH1B1) is an autosomal dominant inherited mutation that causes neurons to fail to migrate properly from the front (anterior) part of the brain. As a result, there will be a smoother frontal lobe. This is common in conditions such as Miller-Dieker syndrome.⁸ 

The DCX gene (also known as Doublecortin) is responsible for tracking the movements of neurons via microtubules (a type of protein). However, mutations to this gene can result in a disruption to the back (posterior) part of the brain. AMABs (assigned male at birth) have full lissencephaly while AFABs (assigned female at birth) often have subcortical band heterotopia.⁹

The ARX gene is crucial for both neuronal migration and brain development. It is most vital for the forebrain. This can cause malformations in the brain, as well as ambiguous genitalia and epilepsy.¹⁰

The RELN gene (Reelin) is responsible for helping neurons layer correctly on the cortex. Mutations can lead to lissencephaly with cerebellar hypoplasia (underdeveloped cerebellum). Either parent can carry this mutation.¹¹

MRI imaging in lissencephaly

MRIs help detect Lissencephaly, particularly by examining the thickness and structure of the cerebral cortex. The cortex is typically 4mm thick; however, with lissencephaly, the cortex is 10-20mm thick. This is due to the neurons incorrectly migrating, resulting in a poorly formed brain. The MRI can also be used to identify sulci and gyri, as well as enlarged ventricles, which may be indicative of abnormal brain formation and poor white matter development.¹²

Differential diagnosis clues: 

Overlapping characteristics can lead to misdiagnosis; therefore, differentiating disorders is crucial for accurate treatment and a clear understanding of prognosis. Examples of differential diagnosis for lissencephaly may include:¹³

• Polymicrogyria 
• Heterotopia 
• Focal cortical dysplasia 

Comparative overview of other cortical malformations 

Polymicrogyria (PMG) is characterised by small, abnormal gyri with disorganised layering. It presents an irregular and bumpy texture on the cortex. Typically, it is asymmetrical and often bilateral, involving the perisylvian region (the region involved in language processing). If there are more sulci on the bumpy surface, then there will be overfolding. 

Pachygyria is a mild form of lissencephaly characterised by the presence of broad gyri, or a thick cortex and with few broad gyri. It is part of the lissencephaly spectrum. 

Schizencephaly presents with a full-thickness cleft from the brain structure to the ventricles. Cerebrospinal fluid-filled (CSF) clefts are typically aligned alongside grey matter. There are two types: open lip and closed lip.¹⁴ 

Role of advanced imaging and diagnostic tools 

MRI Scan 

• T1, T2, and FLAIR are sequences of MRI scans that help visualise cortical thickness and sulcation patterns, as well as the differentiation between grey and white matter in the brain. It is specifically useful for highlighting cortical irregularities
• 3D MRI and surface rendering help with examining the gyri and sulci, revealing folding patterns and structural asymmetry
• Diffusion tensor imaging (DTI) is a type of scan that examines and evaluates the integrity of white matter tracts. It helps assess neuronal connectivity and guide neurosurgical planning
• Functional MRI (fMRI) scans the brain's activity, including the motor and speech areas. It is combined with EEG in epilepsy cases for pre-surgical planning¹⁵ 

CT scan 

• This scan is less sensitive than an MRI. It can identify ventriculomegaly and calcification

Genetic testing 

• Genetic mutations are one of the influencing factors of the development of cortical malformations. Therefore, genetic testing can help with accurate diagnosis during family counselling¹⁶ 

Diagnostic approach 

The stepwise radiologic assessment, where scans are read in a specific order, is initially used to assess the cortical thickness of lissencephaly or pachygyria (characterised by thick folds). The gyri pattern is evaluated based on the absence or broadness of gyri. Full-thickness clefts aligned by the grey matter can help identify schizencephaly based on whether it is a closed-lip or open-lip type. 

To identify ectopic grey matter, such as periventricular heterotopia, nodules near the ventricles would need to be identified. For subcortical band heterotopia, band-like layers would need to be identified.⁷ 

Clinical implications and prognosis 

Prognosis and implications vary based on the type of cortical malformation. Lissencephaly typically presents with severe developmental delay and epilepsy. It can present with complete agyria, which can bring complications such as shortened life expectancy. The current challenge with treating lissencephaly is that there is no curative treatment, as it is genetically influenced. The only way to manage it is through early diagnosis, which helps improve development. 

Other malformations can have different implications and prognoses. For example, polymicrogyria and heterotopia are associated with epilepsy and developmental delays, but have a better prognosis, where some children may live into adulthood. By diagnosing malformations earlier, children can undertake antiepileptic therapy and have surgical plans or rehabilitation.¹⁷ 

Summary 

Cortical malformation diagnoses rely on accurate diagnostic tests and differentiation from other conditions. It helps with understanding the prognosis, management and genetic counselling of the condition. This is because the condition has various types, including lissencephaly, polymicrogyria, heterotopias, and schizencephaly. It can present with overlapping clinical symptoms, making diagnosis more challenging. 

MRI scans help assess characteristics and features that aid in diagnosis. However, they are not always accurate, and genetic counselling helps to make the diagnosis more precise. It can also help with improving developmental implications and prognosis.