MRI_of_a_child_experiencing_seizures._There_are_small_foci_of_grey_matter_Heterotopia_(medicine).html" ;"title="seizure.html" ;"title="MRI of a child experiencing seizure">MRI of a child experiencing seizures. There are small foci of grey matter Heterotopia (medicine)">heterotopia in the corpus callosum, deep to the Cortical dysplasia, dysplastic cortex. (double arrows) Gray matter heterotopias are neurological disorders caused by clumps of gray matter (nodules of neurons) Ectopia (medicine), located in the wrong part of the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

. A grey matter heterotopia is characterized as a type of focal cortical dysplasia. The neurons in heterotopia appear to be normal, except for their mislocation; nuclear studies have shown

glucose metabolism Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms. Carbohydrates are central to many essential metabolic pathways. Pla ...

equal to that of normally positioned gray matter. The condition causes a variety of symptoms, but usually includes some degree of

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

or recurring

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s, and often affects the brain's ability to function on higher levels. Symptoms range from nonexistent to profound; the condition is occasionally discovered as an

incidentaloma In medical or research imaging, an incidental imaging finding (also called an incidentaloma) is an unanticipated finding which is not related to the original diagnostic inquiry. As with other types of incidental medical findings, they may represe ...

when

brain imaging Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Incre ...

performed for an unrelated problem and has no apparent ill effect on the patient. At the other extreme, heterotopia can result in severe seizure disorder, loss of motor skills, and

mental retardation Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

. Fatalities are practically unknown, other than the death of unborn male fetuses with a specific genetic defect.

Preliminary Material: Neurological Development of the Human Fetus

The development of the brain in the human

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal dev ...

is extraordinarily complex and is still not fully understood. Neural matter originates in the outer, ectodermic layer of the

gastrula Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. ...

; thus, it originates from the cell layer primarily responsible for skin, hair, nails, etc., rather than from the layers that develop into other internal organs. The nervous system originates as a tiny, simple open tube called the

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, ...

; the front of this tube develops into the brain (and

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

s of the eye), while the spinal cord develops from the very back end.

Neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

s begin to form early, but most of them become structural rather than active nerve cells. The brain generally forms from the inside-out, especially in the case of the neocortex. The difficulties arising from this are readily apparent, as each successive layer of cells must travel through the previous layer to reach its destination. Therefore, nervous tissue develops ladders made of

radial glial cells Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ol ...

that neurons climb, through the previous layers, to reach their proper destination. Some destinations, such as the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...

, even have "placeholder" neurons that travel up the ladder to form a structure; when the final neurons germinate, they find a correct placeholder and then the placeholder cell dies.

Heterotopia

The complexity of neural development makes it fraught with opportunities for error. Grey matter heterotopia is such an example. It is believed that gray matter heterotopia are caused by arrested migration of neurons to the cerebral cortex; that is, when neurons that are supposed to form part of the cerebral cortex.Many parts of the brain, in addition to the cerebrum, contain grey matter. fail to climb to the end of their ladder correctly and are permanently situated in the wrong location. Gray matter heterotopia are common malformations of cortical development classed as

neuronal migration disorder Neuronal migration disorder (NMD) refers to a heterogenous group of disorders that, it is supposed, share the same etiopathological mechanism: a variable degree of disruption in the migration of neuroblasts during neurogenesis. The neuronal migra ...

s. Heterotopias are classed in two groups: ''nodular'' and ''diffuse''. Nodular types are subependymal and subcortical; diffuse types are termed ''band'' heterotopias. Affected patients are generally divided into three groups, depending on the location of the formation: subependymal, subcortical, and band heterotopia. In addition, especially with heterotopia that are genetically linked, there are gender differences. Men seem to develop more severe symptoms than women with similar formations. In general, band heterotopia, also known as double cortex syndrome, are seen exclusively in women; men with a mutation of the related gene (called XLIS or DCX) usually die

in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albin ...

or have a much more severe brain anomaly. Symptoms in affected women vary from normal to severe developmental delay or intellectual disability; the severity of the syndrome is related to the thickness of the band of arrested neurons. Nearly all affected patients that come to medical attention have

, with partial complex and atypical absence epilepsy being the most common syndromes. Some of the more severely affected patients develop drop attacks.

Periventricular or subependymal

Periventricular means beside the ventricle, while subependymal (also spelled subepydymal) means beneath the

ependyma The ependyma is the thin neuroepithelial ( simple columnar ciliated epithelium) lining of the ventricular system of the brain and the central canal of the spinal cord. The ependyma is one of the four types of neuroglia in the central nervous syst ...

; because the ependyma is the thin epithelial sheet lining the ventricles of the brain, these two terms are used to define heterotopia occurring directly next to a ventricle. This is by far the most common location for heterotopia. Patients with isolated subependymal heterotopia usually present with a seizure disorder in the second decade of life. Subependymal heterotopia present in a wide array of variations. They can be a small single node or a large number of nodes, can exist on either or both sides of the brain at any point along the higher ventricle margins, can be small or large, single or multiple, and can form a small node or a large wavy or curved mass. Symptomatic women with subependymal heterotopia typically present with partial

during the second decade of life; development and neurologic examinations up to that point are typically normal. Symptoms in men with subependymal heterotopia vary, depending on whether their disease is linked to their

X-chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex- ...

. Men with the

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

form more commonly have associated anomalies, which can be neurological or more widespread, and they usually suffer from developmental problems. Otherwise (i.e., in non-X-linked cases) the symptomology is similar in both sexes.

Focal subcortical

Subcortical heterotopia form as distinct nodes in the

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...

, "focal" indicating specific area. In general, patients present fixed neurologic deficits and develop partial epilepsy between the ages of 6 and 10. The more extensive the subcortical heterotopia, the greater the deficit; bilateral heterotopia are almost invariably associated with severe developmental delay or intellectual disability. The cortex itself often has an absence of gray matter and may be unusually thin or lack deep

sulci Sulci or Sulki (in Greek , Steph. B., Ptol.; , Strabo; , Paus.), was one of the most considerable cities of ancient Sardinia, situated in the southwest corner of the island, on a small island, now called Isola di Sant'Antioco, which is, how ...

. Subependymal heterotopia are frequently accompanied by other structural abnormalities, including an overall decrease in cortical mass. Patients with focal subcortical heterotopia have a variable motor and intellectual disturbance depending on the size and site of the heterotopion.

Band form

Like focal subcortical heterotopia, "band" heterotopia form in the white matter beneath the cortex, but the gray matter is more diffuse and is symmetric between the hemispheres. On imaging, band heterotopia appears as bands of gray matter situated between the lateral ventricle and cerebral cortex and separated from both by a layer of normal appearing white matter. Band heterotopia may be complete, surrounded by simple white matter, or partial. The frontal lobes seem to be more frequently involved when it is partial. Patients with band heterotopia may present at any age with variable developmental delay and seizure disorder, which vary widely in severity. Subcortical band heterotopia, also known as "double cortex" syndrome, refers to a band of subcortical heterotopia neurons, located midway between the ventricles and the cerebral cortex. The disorder is seen primarily in females and typically causes varying degrees of intellectual disability and almost all of them have epilepsy. Approximately two thirds of patients with epilepsy ultimately develop intractable seizures.

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

of the brain in subcortical band heterotopia demonstrates two parallel layers of gray matter: a thin outer ribbon and a thick inner band, separated by a very thin layer of white matter between them. The severity of epilepsy and developmental delay is directly correlated with the degree of migration arrest, as indicated by the thickness of the subcortical band heterotopia. Subcortical band heterotopia is caused by mutations in the microtubule-associated DCX gene. The DCX protein is thought to direct neuronal migration by regulating the organization and stability of microtubules, necessary for neuronal motility. The malformation is seen only in females, as the gene is found on the X-chromosome. Since there are two X chromosomes in females, after

X-inactivation X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a ...

, only some neurons lose

doublecortin Neuronal migration protein doublecortin, also known as doublin or lissencephalin-X is a protein that in humans is encoded by the DCX gene. Function Doublecortin (DCX) is a microtubule-associated protein expressed by neuronal precursor cells an ...

function. These neurons with the mutant DCX gene fail to migrate into the cortex and thus form the underlying heterotopic band, while neurons which express the normal gene successfully migrate out to the

cortical plate The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...

. Males with DCX mutations develop classical

lissencephaly Lissencephaly (, meaning "smooth brain") is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in ...

Diagnosis

Detection of heterotopia generally occurs when a patient receives brain imaging—usually an MRI or CT scan—to diagnose seizures that are resistant to medication. Correct diagnosis requires a high degree of radiological skill, due to the heterotopia's resemblance to other masses in the brain.

Treatment

When seizures are present in any forms of cortical dysplasia, they are resistant to medication. Frontal lobe resection provides significant relief from seizures to a minority of patients with periventricular lesions.

Prognosis

In general, gray matter heterotopia is fixed in both its occurrence and symptoms; that is, once symptoms occur, it does not tend to progress. Varying results from surgical resection of the affected area have been reported. Although such surgery cannot reverse developmental disabilities, it may provide full or partial relief from seizures. Heterotopia are most commonly isolated anomalies, but may be part of a number of syndromes, including chromosomal abnormalities and fetal exposure to toxins (including alcohol).