Brain dysgenesis: what it is and what the prognosis is

Brain dysgenesis is a broad umbrella term for congenital anomalies of brain development, ranging from cortical malformations to abnormalities of the corpus callosum, brainstem, and posterior cranial fossa. These conditions are established prenatally and often manifest as developmental delays, epilepsy, movement disorders, behavioral disorders, and learning disabilities. Recent reviews emphasize that although each nosological entity is rare, as a group, dysgenesis is one of the leading causes of childhood drug-resistant epilepsy and disabling neurodevelopmental disorders. [1]

The concept of "cortical developmental malformations" structures most cortical dysgenesis based on stages of embryogenesis: impaired proliferation and apoptosis, neuronal migration, and cortical organization. This approach facilitates the interpretation of neuroimaging data, planning of genetic testing and prognosis, and the selection of surgical tactics for epilepsy. Updated classifications for 2020–2025 have expanded the list of genetic causes and clarified magnetic resonance imaging features. [2]

In addition to the cortex, commissure anomalies (e.g., agenesis of the corpus callosum), midline forebrain division defects, and posterior cranial fossa dysgenesis (cerebellar and brainstem) are widely present. Prenatal ultrasound diagnostics at 18-24 weeks of gestation remains the screening point; however, if malformatio is suspected, targeted neurosonography and fetal magnetic resonance imaging are indicated; in some cases, repeat imaging at 30-32 weeks improves prognosis accuracy. [3]

Understanding of etiology is gradually shifting toward a polygenic and monogenic nature, with the proportion of identified molecular causes increasing thanks to panel sequencing and coelogenetic methods. For families, this means the need for genetic counseling, and for clinicians, the integration of clinical, imaging, and molecular diagnostics into a single decision-making trajectory. [4]

Code according to the International Classification of Diseases, 10th and 11th revisions

In the International Classification of Diseases, Tenth Revision, most cerebral dysgenesis are coded in block Q04, “Other congenital malformations of brain.” This block contains important subheadings: Q04.0, “Congenital malformations of the corpus callosum,” Q04.1, “Arinencephaly,” Q04.2, “Holoprosencephaly,” Q04.4, “Septo-optic dysplasia,” Q04.5, “Megalencephaly,” Q04.6, “Congenital cysts of the brain,” Q04.8, “Other specified malformations of the brain,” and Q04.9, “Congenital malformation of the brain, unspecified.” If necessary, additional codes are included, such as Q03, “Hydrophospital edema.” [5]

In the International Classification of Diseases, Eleventh Revision, congenital anomalies are structured in Chapter 20, "Congenital Anomalies." The coding has become more precise and supports post-coordination, for example, for "cerebral cystic malformations" (LA05.7) and other groups. A dedicated linearization for neurology and an official browser for searching categories are also available. In practice, this helps link the phenotype (e.g., polymicrogyria) with the etiology and associated manifestations. [6]

Table 1. Examples of codes for brain dysgenesis

Classification	Code	Name
ICD 10	Q04.0	Congenital malformations of the corpus callosum (including agenesis)
ICD 10	Q04.2	Holoprosencephaly
ICD 10	Q04.6	Congenital brain cysts
ICD 10	Q04.8 / Q04.9	Other specified/unspecified defects
ICD 11	LA05.7 and others	Cystic malformations of the brain; other headings of Chapter 20 with post-coordination

Epidemiology

A single "overall" prevalence of brain dysgenesis is unavailable due to the heterogeneity of the nosologies; therefore, the frequency of key forms is used as a guide. Agenesis of the corpus callosum is one of the most common anomalies: from 1.8 to 3.3 per 10,000 live births in population registries, and taking into account more sensitive imaging methods, the incidence in neuroimaging is estimated at up to 1 per 4,000 examined individuals. In developmental and epilepsy clinics, the frequency is higher than in the general population. [7]

As a group, cortical malformations are the leading cause of childhood epilepsy. According to current data, approximately 1 in 7 patients with focal epilepsy has a cortical malformation; in childhood and adolescent drug-resistant epilepsy, the proportion reaches "almost half" of cases. This explains the interest in early neurosurgery and minimally invasive techniques. [8]

In posterior cranial fossa anomalies (cerebellar and brainstem), some defects are recognized only in the third trimester or after birth; improvements in fetal magnetic resonance imaging increase detection rates and clarify prognosis. The prevalence of specific forms depends heavily on screening strategies and the availability of neuroimaging. [9]

Table 2. Epidemiological landmarks

Nosology	Approximate frequency of occurrence
Agenesis of the corpus callosum	1.8-3.3 per 10,000 live births; up to 1 per 4,000 according to neuroimaging data
Cortical malformations in focal epilepsy	about 1 in 7 patients
The share of drug-resistant epilepsy in childhood	close to 50%

Reasons

The etiology is diverse: monogenic variants (disorders of genes involved in proliferation, migration, and cortical organization), chromosomal rearrangements, intrauterine infections, and teratogenic effects. High genetic heterogeneity has been described for commissural anomalies (e.g., agenesis of the corpus callosum); the risk is increased by certain syndromes and adverse exposures during pregnancy. [10]

For malformations of cortical development, a "stepwise" causality is key: failure at the proliferation stage results in megalencephaly and certain types of focal cortical dysplasia, at the migration stage—heterotopias and schizencephaly, and at the organization stage—polymicrogyria and pachygyria. Within each cluster, the proportion of identified genetic causes increases with the introduction of sequencing panels. [11]

Posterior fossa anomalies (cerebellar and brainstem) can be part of syndromes or isolated defects; modern reviews emphasize the complexity of morphogenesis and the need for expert interpretation of images in conjunction with genetics. [12]

Risk factors

Non-modifiable factors include a family history of certain syndromes and monogenic diseases. The risk increases if parents have structural chromosome rearrangements, as well as with parental age, especially if some aneuploidies are present. Genetic counseling is recommended for all families when dysgenesis is detected in a fetus or child. [13]

Potentially modifiable factors include infectious agents (intrauterine infections), certain medicinal and toxic influences, and suboptimal pregnancy management. However, even with careful antenatal monitoring, a significant proportion of cases are genetic in nature and not related to external exposures. [14]

Pathogenesis

Pathogenesis reflects the stage at which the failure occurred. When proliferation and apoptosis are impaired, the size and layering of the cortex changes; when migration is impaired, neurons become stuck in the wrong layers, forming, for example, periventricular heterotopias; when organization is disrupted, abnormal convolutions arise (polymicrogyria, pachygyria). These mechanisms disrupt network formation and predispose to epileptogenesis. [15]

Signaling pathways directing fiber growth through midline structures are pathogenetically important for commissural anomalies. In agenesis of the corpus callosum, interhemispheric connections are rebuilt through the anterior commissure and other pathways, but functional compensation is incomplete and variable, explaining the limited symptom complex in some patients and the severe impairments in others. [16]

Symptoms

Clinical manifestations depend on the type and extent of the lesion. Typical symptoms include delayed motor and speech development, epileptic seizures, learning difficulties, and behavioral and attention deficit disorders. Focal forms of cortical dysgenesis are characterized by focal seizures and local neurological signs; diffuse forms are characterized by early generalized epilepsy and profound developmental disabilities. [17]

In agenesis of the corpus callosum, the spectrum ranges from an asymptomatic course to a combination of developmental delay, speech disorders, epilepsy, and visual-spatial difficulties; the prognosis is worse with combined defects. Cerebellar dysgenesis often presents with ataxia, dysarthria, tremor, and cognitive difficulties, especially when combined with brainstem anomalies. [18]

Classification, forms and stages

For cortical dysgenesis, a "stage-by-stage" approach is used: disorders of proliferation/apoptosis, migration, and organization. Within each group, there are subtypes (e.g., focal cortical dysplasia of various types, polymicrogyria, schizencephaly), which helps to develop a diagnostic and treatment pathway, including epilepsy surgery. [19]

Commissural anomalies include complete or partial agenesis and hypogenesis of the corpus callosum and other adhesions. A separate category is posterior cranial anomalies (cystic anomalies, cerebellar dysgenesis, and brainstem anomalies), for which specialized ultrasound and magnetic resonance stratification schemes exist. [20]

Table 3. Simplified clinical and embryological classification

Cluster	Examples	Key stage
Proliferation/apoptosis	megalencephaly, some dysplasias	growth of neurons and glia
Migration	periventricular heterotopia, schizencephaly	radical migration of neurons
Organization	polymicrogyria, pachygyria	formation of convolutions and layers
Commissural	agenesis of the corpus callosum	directed growth of interhemispheric fibers
Posterior cranial fossa	cerebellar/brainstem defects, cystic	morphogenesis of the rhombencephalon

Complications and consequences

The most common complications are drug-resistant epilepsy, intellectual disability, limited independence, and associated behavioral and emotional disorders. Some children develop motor control, speech, and swallowing impairments, particularly in those with brainstem-cerebellar defects. Early initiation of rehabilitation programs significantly improves functional outcomes. [21]

In agenesis of the corpus callosum, the prognosis depends heavily on the isolation of the defect: with isolated forms, some children develop with minimal limitations, while with combined anomalies, the risk of epilepsy and disability is significantly higher. In cortical malformations, early recognition of the focal epileptogenic zone opens a window of opportunity for surgical treatment. [22]

When to see a doctor

Reasons for seeking medical attention include delayed motor and speech development, recurrent paroxysmal events (suspected seizures), regression of skills, atypical prolonged "mutism," and learning and behavioral difficulties. Newborns and infants with macro- or microcephaly, head shape anomalies, and abnormalities on screening ultrasound require early neuroimaging and genetic consultation. [23]

During pregnancy, warning signs include abnormalities of the interhemispheric structures, ventricles, or posterior cranial fossa on routine ultrasound examination. In these situations, targeted neurosonography and fetal magnetic resonance imaging are recommended with the participation of a multidisciplinary team to assess the prognosis and plan pregnancy management. [24]

Diagnostics

Step 1: Clinical examination and anamnesis. Developmental milestones, seizures, behavior, family history, and prenatal data are assessed. Associated defects, visual and auditory functions are clarified. This information guides genetic testing and the selection of imaging protocols. [25]

Step 2. Neuroimaging. For the fetus - targeted neurosonography and fetal magnetic resonance imaging (if suspected at 18-24 weeks and/or repeated at 30-32 weeks). For the child - high-resolution magnetic resonance imaging with protocols for the cortex, commissures, and posterior cranial fossa; in case of epilepsy - magnetic resonance imaging with an epileptological protocol. [26]

Step 3. Genetic diagnostics. For isolated and syndromic forms, sequencing panels, comparative genomic hybridization, and, if necessary, whole-genome sequencing are used. Results are interpreted in conjunction with phenotype and imaging; repeat phenotyping after obtaining molecular data improves accuracy. [27]

Step 4. Epileptological stratification. Electroencephalography, video monitoring, and, in case of drug resistance, invasive mapping (stereoelectroencephalography) to localize the epileptogenic zone with subsequent choice of surgery, laser ablation, or neuromodulation. [28]

Table 4. What we are “looking for” in images by clusters

Cluster	Magnetic resonance imaging signs	Comments
Migration	periventricular heterotopias, slits in schizencephaly	compare with the epilepsy clinic
Organization	"fence" of convolutions in polymicrogyria, smoothing in pachygyria	better visible in the 3rd trimester and postnatally
Commissures	absence/shortening of the corpus callosum, secondary signs	it is necessary to exclude concomitant defects
Posterior fossa	cystic anomalies, cerebellar/brainstem hypoplasia	affects the prognosis of motor skills and speech

Differential diagnosis

During prenatal screening, minor signs can simulate serious defects and vice versa, so repeat neurosonography and fetal magnetic resonance imaging are critical. It is essential to distinguish true cortical defects from the consequences of ischemia and infection, and agenesis of the corpus callosum from severe midline defects such as holoprosencephaly. A consultation with a radiologist, perinatologist, geneticist, and pediatric neurologist is the standard for high-quality differential diagnosis. [29]

In children with seizures, it is important to differentiate between cortical malformations and "latent" epileptogenic pathology without obvious foci on standard magnetic resonance imaging. In such cases, repeat magnetic resonance imaging according to the epileptological protocol and invasive mapping are helpful. In postnatal injuries (stroke, hypoxia-ischemia), the clinical picture may mimic malformations; the diagnosis is determined by the medical history and dynamics. [30]

Table 5. Common "doubles" and how to distinguish them

"It looks like..."	What could it be?	How to distinguish
Polymicrogyria	postischemic cortical scarring	anamnesis, configuration of convolutions, age of detection
Schizencephaly	porencephalic cyst	the presence of gray matter along the walls of the slit
Agenesis of the corpus callosum	severe ventriculomegaly	secondary signs on sagittal sections
Cystic anomaly of the posterior fossa	posthemorrhagic cyst	association with hemorrhage, perinatal history

Treatment

The basic strategy is personalized, interdisciplinary care: early special education, physical therapy, speech therapy, behavioral support, and social services. The earlier interventions begin, the higher the chance of improving adaptive skills, even if the anatomical defect is irreversible. Clear short- and long-term goals, regularly reevaluated, are important for the family.

Drug therapy for epilepsy begins with standard anticonvulsants, tailored to the seizure type and age. In cases of drug resistance (failure to meet seizure control criteria with two adequate medications), surgical options are discussed. Early referral to an epilepsy center improves the chances of remission and progression. [31]

Surgical treatment of focal forms of cortical malformations (e.g., focal cortical dysplasia) remains the most effective method in cases of drug-resistant disease. Current pediatric series demonstrate a high probability of significant seizure reduction and sustained remission with careful selection and mapping. The decision is based on the coordination of magnetic resonance imaging, electroencephalography, and (if necessary) stereoelectroencephalography data. [32]

Stereoelectroencephalography (SEE) has become the standard for invasive mapping in children: it safely localizes the seizure onset zone and helps avoid "major" resections for multilobar and deep lesions. After an unsuccessful initial surgery, SEE can identify residual zones and guide retreatment. [33]

Minimally invasive techniques, primarily magnetic resonance-guided laser interstitial thermotherapy, expand the surgical arsenal for deep lesions and in young children. According to reviews, LITT offers clinically significant remission rates and combines well with stereoelectroencephalography, allowing for a completely minimally invasive approach. For some patients, efficacy is comparable to open resection. [34]

When radical resection is not possible, neuromodulation is considered: vagus nerve stimulation, deep thalamic stimulation, and, in adolescents, responsive neurostimulation under strict indications. These methods reduce the frequency and severity of seizures and improve quality of life, especially in diffuse and multifocal lesions. The choice depends on the seizure phenotype and the distribution of the epileptogenic network. (Review sources emphasize the growing role of combined strategies.)

In newborns and infants with severe posterior fossa malformations and hydrocephalus, the primary goals are CSF shunting interventions, endoscopic ventriculocisternostomy when indicated, and prevention of secondary damage. Correction of CSF flow affects visual, hearing, and motor outcomes, although it does not correct the malformation itself. [35]

Comprehensive rehabilitation is also provided, including physical therapy (postural control, coordination, gait), occupational therapy (sensory integration, daily living skills), speech therapy and alternative communication, and cognitive and behavioral therapy. Individualized educational plans are helpful for schoolchildren; career guidance and social skills are helpful for adolescents. Regular reassessment allows goals to be adjusted to actual progress.

Genetic counseling is a mandatory component. This includes discussion of recurrence risks, molecular verification options, and prenatal and preimplantation diagnostics in future pregnancies. Correct interpretation of genetic results eliminates uncertainty and helps the family plan for the future. [36]

Finally, psychosocial support and referral to resources are just as important as medical interventions. Families need reliable information about prognosis, legal support for accessing care, and adolescents need programs to transition to adult services. Long-term outcomes are better where there is a coordinated "navigator" within the care system.

Table 6. Choice of tactics for epilepsy against the background of dysgenesis

Situation	Preferred tactics	Comments
Focal lesion on magnetic resonance imaging + matched electroencephalography	resection/discectomy of the lesion	high probability of remission with correct localization
Deep/hard to reach focus	laser interstitial thermotherapy (with or without stereoelectroencephalography)	minimal invasion, especially in children
Multifocal network	neuromodulation (vagus nerve stimulation, deep stimulation, reciprocal neurostimulation)	reduction in the frequency and severity of attacks
Focal-free magnetic resonance imaging but persistent drug resistance	stereoelectroencephalography to clarify the network	increases the chance of subsequent surgical assistance

Prevention

There is no specific primary prevention for most genetically determined forms, but good pregnancy management, vaccination as indicated, avoidance of known teratogens, and infection control reduce the risk of adverse outcomes. Couples with a previously affected child are advised to undergo genetic counseling before planning a subsequent pregnancy. [37]

Secondary prevention of complications includes early rehabilitation, injury and fall prevention, nutritional and sleep management, timely hearing and vision correction, and early referral to an epilepsy center if signs of drug resistance are detected. These measures do not correct the anatomical defect, but they significantly improve the developmental trajectory.

Forecast

The prognosis is determined by the type and extent of the defect, the presence of associated anomalies, and the timing of intervention. With isolated agenesis of the corpus callosum, the outcome varies from near-normal development to moderate impairment, while combined forms carry a high risk of epilepsy and developmental delay. With focal cortical defects, early surgery significantly increases the chance of remission and improved neurodevelopment. [38]

Prenatal diagnostic testing and multidisciplinary counseling improve family awareness and enable planning of delivery and early intervention. Minimally invasive neurosurgical technologies and neuromodulation expand the range of treatment options for children previously considered "inoperable." [39]

Table 7. Positive and negative forecast factors

Factor	Influence
Isolation of the defect (without other anomalies)	better cognitive outcomes
Early diagnosis and intervention	higher chance of developing skills
Coordinated epileptological network and localizable focus	higher chance of remission after surgery
Generalized and multiple defects, severe epilepsy	cautious forecast

FAQ

Is this a lifelong diagnosis?
Anatomical defect, yes, but the functional trajectory is highly variable. Early rehabilitation and, if indicated, epilepsy surgery can radically improve quality of life. [40]

Is it possible to "cure" cerebral dysgenesis?
The congenital anomaly cannot be corrected, but its consequences can be treated: seizures can be controlled, speech and motor skills can be developed, and limitations can be minimized. Minimally invasive technologies are expanding the possibilities. [41]

Will agenesis of the corpus callosum always cause severe problems?
No. In the isolated form, some children develop close to normal, but combined anomalies dramatically worsen the prognosis—these are the ones actively sought in magnetic resonance imaging and genetics. [42]

How effective is surgery for cortical malformations?
With properly localized epileptogenic zones, the chance of a significant reduction in seizures is very high, and in some cases, long-term remission is achieved; LITT and stereoelectroencephalography increase the number of candidates for minimally invasive interventions. [43]