Polymicrogyria (PMG) is a congenital disorder of cortical development that affects the structure of the brain. It arises from abnormal development of the cerebral cortex before birth, resulting in a disorganized brain surface. The name translates from Greek as “many small folds” (poly- many, micro- small, -gyria folds). This malformation results from errors in the final stages of neuronal migration or early cortical organization during fetal development.
The Structural Abnormality in the Brain
The normal human brain surface features large, undulating folds called gyri, separated by grooves known as sulci. In contrast, a brain affected by polymicrogyria is characterized by an excessive number of folds that are irregularly small and often shallow. These miniature folds appear tightly packed together, frequently causing the cortex surface to look thickened and simplified on imaging. This appearance is often due to the small folds fusing together.
This abnormal folding pattern results in a profound disorganization of the cerebral cortex’s internal structure. The typical mammalian cortex is organized into six distinct cellular layers, each with specialized functions. In areas affected by PMG, this normal six-layered lamination is disrupted, replaced by a disorganized appearance that often features a four-layered or, less commonly, a two-layered structure.
The fusion of the molecular layer across the shallow sulci is a common histological feature, contributing to the disorganized appearance. The underlying white matter is also affected, often showing an ill-defined boundary where the grey matter meets the white matter beneath it. This structural alteration means the affected areas of the brain cannot process information efficiently compared to a normally formed cortex.
Causes and Categorization
The underlying reasons for polymicrogyria are diverse, involving both genetic and acquired factors that disrupt brain development in utero. Genetic causes include mutations in specific genes, such as ADGRG1 (formerly GPR56), which are important for neuronal migration and cortical layer formation. Dozens of genes have been linked to PMG or related malformations, with inheritance patterns ranging from autosomal recessive to autosomal dominant.
Acquired factors involve an environmental insult to the developing fetal brain, typically occurring between 17 and 26 weeks of gestation. Prenatal infections, particularly with Cytomegalovirus (CMV), are recognized as one of the most common acquired causes of the malformation. Intrauterine ischemia, or a lack of oxygen and blood supply to the fetal brain, can also cause the damage that leads to polymicrogyria.
The condition is categorized based on the location and extent of the structural abnormality within the brain. It can be unilateral, affecting only one hemisphere, or bilateral, affecting both sides of the brain. Bilateral forms are further classified into distinct syndromes based on the affected region, such as bilateral perisylvian PMG, which is the most common pattern, or bilateral frontoparietal PMG.
The most severe form is bilateral generalized polymicrogyria, which affects the entire brain’s surface. Conversely, a milder type, unilateral focal polymicrogyria, affects a small, localized area on one side. This categorization is important because the location of the malformation strongly correlates with the types of symptoms a person will experience.
Clinical Manifestations
The functional impact of polymicrogyria varies widely among individuals, depending directly on the brain regions involved and the overall extent of the malformation. Neurological symptoms can range from subtle deficits to profound developmental challenges. Seizures are the most common symptom, with approximately 90% of individuals with PMG developing epilepsy at some point, often beginning in childhood.
The type of seizure experienced depends on the location of the malformation; for instance, focal PMG often leads to focal seizures, while bilateral involvement can result in more complex seizure types. Developmental delay is also highly prevalent, affecting both cognitive and motor skills. Individuals may experience difficulties with muscle coordination, movement, and general intellectual functioning.
Specific patterns of PMG lead to specific functional impairments. Bilateral perisylvian PMG, which affects the areas around the Sylvian fissure, is frequently associated with problems concerning the facial, pharyngeal, and masticatory muscles. This can result in significant speech and language difficulties, feeding issues, and problems with swallowing, sometimes requiring specialized communication aids.
The severity of the symptoms is generally greater in bilateral forms of the condition. Bilateral generalized PMG, for example, is often linked to severe intellectual disability and seizures that are difficult to control with medication. Other possible complications include visual impairment, respiratory issues, and co-occurring diagnoses like cerebral palsy.
Diagnosis and Management
Diagnosis of polymicrogyria relies primarily on medical imaging. High-resolution Magnetic Resonance Imaging (MRI) is the standard method for confirming the condition. MRI clearly reveals the abnormal cortical folding, thickened appearance, and irregular junction between the grey and white matter. Specialized MRI sequences have improved the ability of clinicians to identify this malformation.
For individuals experiencing seizures, an Electroencephalogram (EEG) is employed to evaluate the brain’s electrical activity and help determine the specific type of epilepsy present. Genetic testing is also often considered, as identifying an underlying gene mutation or chromosomal abnormality can provide information about the cause and potential inheritance pattern.
The management of PMG is focused on providing supportive and symptomatic care, as the structural malformation itself cannot be reversed. Anti-epileptic medications are the first line of treatment to control seizures, with the choice of drug tailored to the seizure type. For individuals with drug-resistant epilepsy, alternative treatments like the ketogenic diet or vagus nerve stimulation may be explored.
Comprehensive therapy is fundamental to addressing developmental and functional delays. Physical therapy helps with gross motor impairment, while occupational therapy focuses on fine motor difficulties. Speech therapy is essential for managing language deficits and swallowing problems. This collaborative approach, involving multiple specialists, aims to help individuals achieve their highest possible level of function.