MRI of a child experiencing heterotopia in the corpus callosum">seizure">MRI of a child experiencing seizures. There are small foci of grey matter heterotopia in the corpus callosum, deep to the Cortical dysplasia">dysplastic cortex. (double arrows)">Heterotopia (medicine)">heterotopia in the corpus callosum, deep to the Cortical dysplasia">dysplastic cortex. (double arrows) Gray matter heterotopia is a neurological disorder caused by gray matter being located in an atypical location in the brain. Grey matter Heterotopia (medicine), heterotopia is characterized as a type of focal cortical dysplasia. The

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

in heterotopia are otherwise healthy; nuclear studies have shown

glucose metabolism Glucose is a sugar with the molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae during photosynthesis from water and ...

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 disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

or recurring

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s, and often affects the brain's ability to function. Symptoms vary in severity; 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. In other cases, heterotopia can result in severe seizure disorders, loss of motor skills, and intellectual disability.

Background

During fetal development, neural matter originates in the outer,

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...

ic 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 Cell (biology), cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered e ...

; 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 folds become elevated, ...

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

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

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

Neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

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 neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...

. Due to the nature of the process, disruptions can result in heterotopia, as the neurons have to migrate through many layers to reach their destination. Therefore, nervous tissue develops ladders made of radial glial cells 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. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

, 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. 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 an interruption in the migration of neurons to the cerebral cortex.Many parts of the brain, in addition to the cerebrum, contain grey matter.

Types

Gray matter heterotopia are common malformations of cortical development known 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 sex differences. Men seem to develop more severe symptoms than women with similar formations. Band heterotopia, a form of the condition (also known as double cortex syndrome), is seen exclusively in women; men with a mutation of the related gene (called XLIS or DCX) usually die

in utero The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic and fetal development of one or more fertilized eggs until bir ...

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 s ...

; 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 chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

. Men with the

X-linked Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...

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 that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...

, "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 , Stephanus of Byzantium, Steph. B., Ptolemy, Ptol.; , Strabo; , Pausanias (geographer), Paus.), was one of the most considerable cities of ancient Sardinia, situated in the southwest corner of the island, on a small isla ...

. 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.

Diagnosis

Detection of heterotopia generally occurs when a patient receives brain imaging—usually an MRI or

CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...

—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).