CNS malformations

Definition

History

Etiology

Classification

Clinical Manifestations

Diagnosis

Treatment and Management strategies

Conclusion

Author

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Definition:

Central nervous system malformations, or congenital CNS anomalies, are structural abnormalities in the brain and spinal cord during the embryological and fetal period. They can result from genetic or environmental factors, or both, and can significantly impact neurological function and developmental milestones. Understanding their classification is not just a matter of academic interest; it is crucial for accurate diagnosis, effective treatment, and advancing research in this field. Numerous individuals present with minor central nervous system malformations that have no significant clinical impact or implications. This classification can be based on anatomical, topological or histopathological criteria.

History:

The history of understanding central nervous system (CNS) malformations spans centuries and reflects the evolving knowledge of anatomy, embryology, pathology, and genetics. These malformations, which include structural abnormalities of the brain and spinal cord, have fascinated scientists and physicians due to their profound impact on human development and function. 

Ancient Period: Ancient texts describe congenital malformations, including CNS defects. For example, the Egyptians and Greeks recognized conditions like hydrocephalus (an abnormal fluid buildup in the brain) and possibly other malformations. However, a lack of anatomical knowledge limited their understanding.

Hippocrates (460–370 BC): Often regarded as the "Father of Medicine," Hippocrates and his followers speculated about the role of the brain in controlling bodily functions. However, specific CNS malformations were not well understood at the time. 

Medieval Period: With limited knowledge of neuroanatomy, explanations for malformations were often rooted in religious or superstitious beliefs. Many congenital conditions were attributed to supernatural causes, and little scientific inquiry was conducted into the etiology of these disorders.

Renaissance and Early Modern Periods Vesalius (1514–1564): Andreas Vesalius, a pioneering anatomist, advanced the study of human anatomy, including the brain and spinal cord, through his detailed dissections and illustrations. During this period, he began a more systematic study of the CNS. 

Thomas Willis (1621–1675): Considered one of the founders of neurology, Willis made significant contributions to understanding the brain's vascular system, including the Circle of Willis, and laid the groundwork for understanding CNS malformations related to blood flow and development. 

18th and 19th Centuries: During these centuries, advances in embryology helped to clarify the stages of human development and the formation of the neural tube, which is crucial for understanding CNS malformations. Scientists began to realize that disruptions in early neural tube closure could lead to conditions like spina bifida and anencephaly. 

Virchow and the Cellular Basis of Disease: Rudolf Virchow's work in the mid-19th Century established that diseases, including malformations, could be understood at the cellular level. This shift in thinking led to the recognition that CNS malformations result from abnormal cell development and tissue organization during embryogenesis. John Cleland (1835–1925). Cleland, a Scottish anatomist, described several neural tube defects and congenital CNS malformations, advancing the field of neuropathology by providing detailed descriptions of conditions such as encephalocele and myelomeningocele. 

20th Century Neurosurgery and Imaging Advances: The 20th Century saw significant progress in diagnosing and treating CNS malformations. Neurosurgical techniques and the development of imaging technologies like CT scans and MRI allowed for better visualization of brain and spinal cord anomalies. This led to earlier and more accurate diagnoses of conditions like Dandy-Walker malformation, Chiari malformation, and holoprosencephaly.

Genetics and Molecular Biology: The rise of genetics and molecular biology in the latter half of the 20th Century revolutionized the understanding of CNS malformations. Researchers identified genetic mutations and chromosomal abnormalities responsible for various congenital disorders, such as tuberous sclerosis, Joubert syndrome, and lissencephaly. The discovery of the role of folic acid deficiency in neural tube defects like spina bifida also led to significant public health interventions. 

21st Century and Current Research Genomic Medicine: With the completion of the Human Genome Project and advances in genomic technologies, the 21st Century has identified numerous genetic pathways involved in CNS development. Mutations in genes regulating processes like neuronal proliferation, migration, and differentiation have been linked to megalencephaly, hemimegalencephaly, and microcephaly.

Stem Cell Research and Regenerative Medicine: Current research into stem cells and tissue engineering holds promise for understanding CNS malformations at the cellular level and potentially developing therapeutic interventions in the future.

Public Health Initiatives: Continued efforts to prevent neural tube defects through prenatal care, including folic acid supplementation and improved prenatal screening techniques, have reduced the incidence of specific CNS malformations worldwide.

Etiology: 

The etiology of central nervous system (CNS) malformations is often multifactorial, encompassing genetic and chromosomal abnormalities, environmental exposures (such as infections, toxins, and radiation), nutritional deficiencies (such as folic acid deficiency), and hypoxic-ischemic events during the embryological period. Hypoxia and ischemia, in particular, can result in an energy deficit that impairs neuronal migration and organization.

Diagnosis:

Diagnosis typically involves a combination of: 

• Prenatal Imaging: Ultrasound and MRI can identify many brain malformations before birth.
• Postnatal Imaging: MRI and CT scans help diagnose and further characterize brain malformations.
• Genetic Testing: Identifying specific genetic mutations or syndromes associated with brain malformations.

Classification:

Histopathological classification of central nervous system (CNS) malformations can be organized according to the cellular origin of the affected tissues. These categories include malformations of ectodermal, epithelial, endothelial, and mesenchymal origin. In numerous cases of CNS-malformations the combination of different cellular origins are involved.

Additionally, alternative classification systems may be based on functional impairments, isolated anomalies, or association with syndromic conditions.

Malformations with ectodermal cell origin

Ectodermal malformations involving the central nervous system (CNS) arise from aberrant development of the ectoderm, one of the three primary germ layers in the early embryonic stage. The ectoderm is responsible for the formation of both the nervous system, encompassing the brain and spinal cord, and the integumentary system, including the skin and its appendages (hair, nails, and glands). Disruptions in the development of ectodermal derivatives, particularly within the CNS, can result in a spectrum of congenital neurological disorders.

Neural Tube Defects (NTDs)

NTDs occur when the neural tube forms the brain and spinal cord and fails to close properly during early embryonic development. Key examples include:

• Anencephaly: A severe condition where significant parts of the brain, skull, and scalp are missing. It is a result of the neural tube failing to close at the cranial end.
• Encephalocele: saccular protrusions of part of the brain and the membranes that cover it through openings in the skull.
• Spina Bifida: A condition where the spinal column does not close completely, which can also involve the brain in severe cases (e.g., Chiari malformation and hydrocephalus). The spinal cord does not close completely, which can lead to protrusion of the spinal cord and its meninges (meningocele). 

Migration disorders Lissencephaly

"Smooth brain" where the brain lacks the usual folds and grooves due to abnormal neuronal migration.

• Polymicrogyria: The presence of numerous small gyri (folds) on the brain's surface.
• Heterotopia: Clusters of neurons in the wrong location due to improper migration during development.

Disorders of Cortical Organization

• Focal Cortical Dysplasia: Abnormal development of the cerebral cortex, leading to areas of disorganized structure and function. Taylor type and non-Tylor type.
• Schizencephaly: Characterized by clefts or splits in the cerebral hemispheres, which can lead to abnormal communication between different brain parts.

 Midline Malformations

• Agenesis of the Corpus Callosum: Absence of the corpus callosum (partial or complete), the structure that connects the two cerebral hemispheres.
• Septo-Optic Dysplasia: A condition involving underdevelopment of the optic nerves, pituitary gland abnormalities, and absence of the septum pellucidum.
• Holoprosencephaly: It is a spectrum of disorders characterized by the incomplete separation of the cerebral hemispheres. It results from the forebrain's (prosencephalon) failure to divide into the two hemispheres properly during early development. This can lead to a range of symptoms, from mild facial anomalies to severe brain malformations and cognitive impairment.

- Semilobar: A partial division of the hemispheres.

- Lobar: The least severe form with near-complete division of the hemispheres but some fusion at the frontal lobes. Cranial Dysraphism

- Alobar: The most severe form where the brain fails to divide into the right and left hemispheres. In rare cases it can lead to cyclopia.

Cyclopia

It is a rare congenital disorder characterized by the incomplete development of the brain and face, particularly the eyes. In this condition, the fetus develops a single eye or a fused pair of eyes in the middle of the forehead. Cyclopia occurs when the forebrain (prosencephalon) fails to divide appropriately into two hemispheres during early fetal development, a condition known as holoprosencephaly. 

Critical features of cyclopia include:

1- Single eye or fused eyes: The most noticeable characteristic of cyclopia is the presence of one central eye, or a partial fusion of two eyes, in the forehead area. 

2- Absence of a nose: Often, the nose may be either absent or underdeveloped, replaced by a proboscis-like structure above the eye. 

3- Severe facial abnormalities: Other facial features may also be malformed due to improper development. 

4- Incompatibility with life: Cyclopia is almost always fatal, as the underlying brain abnormalities are severe. Most affected fetuses do not survive long after birth, if at all. 

Cyclopia can be genetic or environmental, caused by chromosomal abnormalities, genetic mutations, or exposure to certain toxins during pregnancy.

Posterior Fossa Malformations

• Chiari Malformations: Structural defects in the cerebellum where it protrudes into the spinal canal.
• Dandy-Walker Malformation: Involves the cerebellum and the fluid-filled spaces around it, leading to an enlarged fourth ventricle, absence of the cerebellar vermis (partial or complete), and cyst formation near the internal base of the skull.
• Joubert Syndrome: A genetic disorder that affects the cerebellum and brainstem, it is characterized by the "molar tooth sign" on brain imaging, which indicates structural abnormalities in these regions. Symptoms include impaired balance and coordination, abnormal eye movements, developmental delays, breathing irregularities, and cognitive impairment.
• Cerebellar Hypoplasia: This refers to incomplete or underdeveloped cerebellum. It can be isolated or occur with other abnormalities. Difficulty with motor control, discoordination (ataxia), poor muscle tone (hypotonia), delayed milestones, and sometimes intellectual disability are some manifestations.
• Rhombencephalosynapsis: It is a rare congenital disorder in which the cerebellar vermis is absent, and the hemispheres of the cerebellum are fused. It is linked to poor motor coordination, muscle stiffness, and developmental delays.

Neurocutaneous Syndromes 

These syndromes involve abnormalities in both the nervous system and the skin, reflecting the ectodermal origin of both tissues. Examples include:

• Neurofibromatosis is a genetic disorder characterized by the growth of non-cancerous tumors along nerves in the skin, brain, and other body parts. It can also involve brain malformations.
• Tuberous Sclerosis: Condition that causes benign tumors in the brain and other vital organs, often accompanied by skin abnormalities.
• Sturge-Weber Syndrome (SWS): A rare congenital disorder involving abnormal blood vessel development affecting the skin, brain, and eyes. It is characterized by a facial port-wine stain (usually involving the trigeminal nerve distribution) and leptomeningeal angiomas (vascular malformations in the brain). Neurological complications include seizures, stroke-like episodes, and developmental delays.
• Von Hippel-Lindau Disease (VHL): This genetic condition is marked by the formation of tumors and cysts in various parts of the body, including the brain, spinal cord, and retina. Hemangioblastomas (blood vessel tumors) are common in the CNS, and the condition may lead to vision problems, balance issues, and neurological deficits.
• Incontinentia Pigmenti: Genetic disorder that affects the skin, hair, teeth, nails, and CNS. It often presents with a characteristic pattern of skin changes (blistering, wart-like rashes, and pigmentation changes), along with potential neurological complications such as seizures, developmental delays, and intellectual disabilities. 
• Hypomelanosis of Ito: Rare neurocutaneous syndrome characterized by streaks or patches of hypopigmentation along the lines of Blaschko. It is often associated with neurological abnormalities such as intellectual disability, seizures, and musculoskeletal deformities.

Brain overgrowth disorders (neuronal proliferation disorders)

- Megalencephaly 

Variable Manifestations: It can be isolated (not associated with other symptoms) or syndromic (associated with other physical or neurological symptoms).

Potential Symptoms: Depending on the underlying cause, symptoms can include developmental delays, seizures, intellectual disabilities, and motor coordination issues.

Causes: Megalencephaly can result from various factors, including mutations in genes that regulate brain growth and development. It is often associated with overgrowth syndromes and may co-occur with conditions such as:

• Tuberous Sclerosis Complex (TSC)
• Neurofibromatosis Type 1 (NF1)
• Sotos Syndrome
• Beckwith-Wiedemann Syndrome (BWS)
• Coffin-Lowry Syndrome
• Macrodystrophia Lipomatosis
• Cowden Syndrome
• Meier-Gorlin Syndrom
• Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Metabolic Disorders: Conditions that affect metabolism can also lead to brain enlargement (Alexander disease)

Hemimegalencephaly  

It is a rare congenital neurological condition where one half of the brain (hemisphere) is abnormally more significant than the other. This overgrowth of one side of the brain can lead to significant neurological symptoms, including epilepsy, developmental delays, and motor impairments. The condition is considered a form of cortical dysplasia, a developmental malformation of the brain.

Neurological Symptoms: These can include frequent and severe seizures, hemiparesis (weakness on one side of the body), and cognitive impairments. Affected individuals often experience delays in reaching developmental milestones.

Causes: The exact cause of hemimegalencephaly is not fully understood, but it is thought to involve mutations in genes that regulate brain development and cell growth, such as AKT3, MTOR, or PIK3CA genes.

Neurocristopathies

The neural crest is a transient, multipotent group of cells that arises from the ectoderm—the outermost layer of the embryo—during vertebrate development. These cells originate along the neural tube, which eventually forms the central nervous system, and then migrate to various body parts. Neural crest cells give rise to a wide variety of tissues and structures, including:

• The peripheral nervous system (sensory and autonomic ganglia, Schwann cells)
• Pigment cells (melanocytes in the skin)
• Facial cartilage and bones Some endocrine glands (such as the adrenal medulla)
• Parts of the heart (such as the outflow tract)

Neural crest disorders arise from abnormalities in a specialized group of ectodermal cells known as the neural crest. These play a crucial role in developing the peripheral nervous system and other body tissues. While these disorders predominantly impact peripheral nerves, however as heterogenous conditions may involve brain malformations and lead to functional impairments.

Epithelial cell malformation can refer to conditions involving abnormal development, differentiation, or functioning of epithelial cells in the CNS. Epithelial cells in the CNS include ependymal cells and choroid plexus epithelial cells. These cells line the brain's ventricles and the spinal cord's central canal, playing crucial roles in producing and regulating cerebrospinal fluid (CSF). Some critical conditions involving malformation or dysfunction of these cells include:

Ependymomas

These tumors arise from ependymal cells. They can occur in any part of the CNS but are commonly found in the brain and spinal cord. Ependymomas may cause symptoms by obstructing CSF flow, leading to hydrocephalus, or by directly compressing neural structures.

Choroid Plexus Papilloma/Carcinoma

Tumors arising from the choroid plexus epithelial cells can lead to overproduction of CSF, resulting in hydrocephalus. Choroid plexus papillomas are generally benign, while carcinomas are malignant. 

Hydrocephalus

While not always a direct result of epithelial cell malformation, hydrocephalus can occur due to dysfunction or blockage caused by tumors or malformations in the ependymal lining, affecting CSF flow and absorption. 

Ciliopathies

Ependymal cells possess cilia, which are essential for the movement of CSF. Malformations or dysfunctions in these cilia can lead to problems with CSF circulation, potentially contributing to conditions like hydrocephalus or other neurological disorders.

Kartagener syndrome is a specific form of primary ciliary dyskinesia (PCD), a ciliopathy affecting the function of cilia, the microscopic hair-like structures that line the respiratory tract and other parts of the body.

A triad of symptoms characterizes Kartagener syndrome: Situs Inversus, Chronic sinusitis and bronchiectasis. Other accompanied symptoms are infertility, hearing loss and recurrent respiratory tract infections.

Malformations with endothelial cell origin

Malformation or dysfunction of endothelial cells in the brain can lead to various vascular disorders, which can have significant neurological implications. Endothelial cells line the blood vessels, including those in the brain, and play critical roles in maintaining vascular integrity, regulating blood-brain barrier (BBB) function, and controlling blood flow. 

Cerebral Cavernous Malformations (CCM)

Cerebral cavernous malformations (CCMs) are not to be underestimated. These clusters of abnormally dilated blood vessels in the brain, characterized by a 'cavernous' structure, can cause a range of neurological symptoms, including seizures, headaches, neurological deficits, and even hemorrhagic stroke if they rupture. The potential severity of these conditions underscores the importance of our research in understanding and treating them.

Arteriovenous Malformations (AVM)

AVMs are abnormal, tangled connections between arteries and veins that bypass the normal capillary system. These malformations can lead to improper blood flow and an increased risk of bleeding in the brain. The endothelial cells in AVMs are often structurally and functionally abnormal, contributing to the instability of these vessels. AVMs can cause headaches, seizures, and neurological deficits, and in severe cases, they can lead to hemorrhagic stroke. 

Capillary Telangiectasias

Tiny, dilated capillaries within the brain can occur as isolated lesions or as part of a syndrome, such as hereditary hemorrhagic telangiectasia (HHT). Capillary telangiectasias usually have a standard endothelial lining but may be associated with bleeding or calcification. Dilated capillaries are commonly observed within the brainstem or spinal cord and typically remain asymptomatic.

However, in cases where symptoms do arise, they are generally attributed to minor hemorrhages. Magnetic resonance imaging (MRI) is the imaging modality of choice for their detection and assessment. Management is predominantly conservative, with surgical or interventional treatment being rarely necessary.

The blood-brain barrier (BBB) Dysfunction

The BBB is a selective permeability barrier formed by endothelial cells that regulate the movement of substances between the bloodstream and the brain. Due to malformation or damage to endothelial cells, dysfunction of the BBB can result in increased permeability. This may allow toxins, pathogens, and immune cells to enter the brain, potentially leading to inflammation, neurodegeneration, and conditions like multiple sclerosis or Alzheimer's disease.

Cerebral Small Vessel Disease (SVD)

This condition involves the small blood vessels in the brain, including arterioles, capillaries, and venules. Endothelial cell dysfunction in these vessels can lead to reduced cerebral blood flow, white matter lesions, and microbleeds. SVD is a significant cause of stroke and dementia and is associated with a range of symptoms, from cognitive decline to gait disturbances.

Malformations with mesenchymal cell origin

Mesenchymal CNS malformations are a group of congenital abnormalities that affect the central nervous system (CNS) and involve the mesenchymal tissue. Mesenchymal or connective tissue includes structures such as blood vessels, muscles, and the supporting tissues around organs and nerves. These malformations can encompass a range of conditions, including:

Meningeal Abnormalities

The meninges are protective layers covering the brain and spinal cord. Abnormalities in these layers can lead to conditions such as:

• Meningocele: A type of spina bifida where the meninges protrude through a defect in the spine.
• Meningoencephalocele: A condition where both meninges and brain tissue protrude through a skull defect.

Vascular Malformations

Vascular malformations in the central nervous system (CNS) are abnormal clusters of blood vessels that occur in the brain or spinal cord. These malformations can vary in size, location, and severity, leading to various neurological symptoms depending on their nature and location. There are several types of CNS vascular malformations, each with distinct characteristics:

- Arteriovenous Malformations (AVMs):

• Description: Abnormal tangles of arteries and veins with no intervening capillary bed.
• Pathophysiology: Blood flows directly from arteries to veins without the usual slow-down through capillaries, leading to high-pressure flow.
• Symptoms: Can cause headaches, seizures, neurological deficits, and hemorrhages (brain bleeds) due to the fragile nature of the vessels.
• Diagnosis: MRI, CT scans, and cerebral angiography.
• Treatment: Options include surgical resection, endovascular embolization, and stereotactic radiosurgery.

- Cavernous Malformations (Cavernomas): 

• Description: Clusters of dilated, thin-walled blood vessels.
• Pathophysiology: These lesions have a slow blood flow and are prone to leaking small amounts of blood.
• Symptoms: May cause headaches, seizures, and focal neurological deficits; often present with microhemorrhages.
• Diagnosis: Best detected using MRI, particularly with gradient-echo sequences.
• Treatment: Observation for asymptomatic cases; surgical removal for symptomatic or hemorrhagic cases.

- Venous Malformations (Developmental Venous Anomalies - DVAs): 

• Description: Anomalous veins draining normal brain tissue.
• Pathophysiology: Typically benign and asymptomatic, but can occasionally cause issues if associated with other vascular malformations.
• Symptoms: Rarely symptomatic. 
• Diagnosis: Detected incidentally on MRI or CT scans.
• Treatment: Usually not treated unless associated with other symptomatic vascular malformations.

- Dural Arteriovenous Fistulas (DAVFs) 

• Description: Abnormal connections between dural arteries and venous sinuses or meningeal veins.
• Pathophysiology: Can cause increased venous pressure and congestion.
• Symptoms: It may lead to headaches, tinnitus, and neurological deficits, and there is a higher risk of hemorrhage in certain locations.
• Diagnosis: Detected using MRI, MR angiography, and digital subtraction angiography (DSA).
• Treatment: Options include endovascular therapy (embolization), surgery, or radiosurgery.

Mesenchymal Dysplasia

Abnormal growth or development of mesenchymal tissue can affect various CNS parts and lead to structural deformities or functional impairments.

Arachnoid Cysts

Fluid-filled sacs within the arachnoid membrane. Often asymptomatic, but can cause headaches, seizures, or neurological deficits if they exert pressure on the brain

Dural Ectasia

Widening or ballooning of the dural sac, often seen in connective tissue disorders like Marfan syndrome The symptoms include back pain, headaches, or neurological symptoms due to nerve compression.

Hydrocephalus can manifest in various forms and may result from abnormalities involving ectodermal, epithelial, endothelial, or mesenchymal cell development.

Clinical Manifestations: 

The clinical presentation of CNS malformations exhibits considerable variability, contingent upon the specific type and severity of the malformation. Symptoms may encompass developmental delays, intellectual disabilities, seizures, motor deficits, behavioral disturbances, and other neurological impairments. It is noteworthy that many individuals with minor malformations may remain asymptomatic.

Diagnosis:

Diagnosis typically involves a combination of:

• Prenatal Imaging: Ultrasound and MRI can identify many brain malformations before birth.
• Postnatal Imaging: MRI and CT scans help diagnose and further characterize brain malformations.
• Genetic Testing: Identifying specific genetic mutations or syndromes associated with brain malformations

Treatment and Management Strategies:

• Medical Management: Anticonvulsants for seizure control and medications for associated symptoms such as concentration deficit and behavioral disturbances.
• Surgical Interventions: Correction of structural abnormalities, surgical treatment of refractory epilepsy, shunt placement for hydrocephalus.
• Therapies: Physical, auditory, visual, occupational, and speech therapy to address developmental and functional impairments.

Conclusion:

Brain malformations are varied in both presentation and cause, making classification challenging. However, this complexity opens avenues for further research and insight. Advances in imaging, genetics, and prenatal care are improving the diagnosis and treatment of these conditions, offering hope for better patient outcomes.

By AmirHossein Mahdavian MD,

Pediatric neurologist