Neuronal Migration Defects

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Pathogenesis and Pathophysiology. Anomalous cerebral cortical development is generally characterized as a cortical migrational abnormality, although an actual defect in migration has yet to be conclusively demonstrated. Rorke y has hypothesized a variety of factors that must be considered in the pathogenesis of cortical migrational abnormalities. Among the various components of development, cellular proliferation, cell death, postmigrational intracortical growth and development, and extracellular matrix abnormalities can each be implicated as a possible pathogenetic mechanism.

The cortical migrational abnormalities can be grouped into three general categories: lissencephaly/pachygyria, polymicrogyria, and heterotopia. Lissencephaly and pachygyria are thought to represent a spectrum of the same basic disorder: lissencephaly referring to a diffuse bilateral abnormality of development, and pachygyria being a focal or multifocal abnormality with similar features ( F!g...28z5 ). Radiographically and on gross pathological examination, the normal gyral and sulcal pattern is effaced by a smooth agyric surface. The cerebral cortex is markedly thickened with variable preservation of the cerebral white matter. At least two distinct types of lissencephaly exist. Type II lissencephaly (see later) is pathologically characterized by diffuse agyria, although focal polymicrogyria may also be present. Cross sections show the cerebral hemisphere to be approximately one half gray matter and one half white matter (see Fig,..28-5 ). The junction between the gray and white matter is usually blurred, and nodules of gray matter heterotopia are commonly seen in the white matter. Type I lissencephaly is classically associated with the Miller-Dieker syndrome, although autosomal recessive and X- linked forms have been identified. Type I lissencephaly, independent of the inheritance pattern, shows similar histopathological features. The cortex is extremely thick at the expense of the cerebral white matter, and the cortex is organized into four abnormal layers. The Miller-Dieker syndrome has been mapped to 17p13, and the putative gene cloned by Reiner and colleagues. However, the function of this gene, called LISI, is not known at this time. In contrast to type I lissencephaly, in which the remainder of the brain is relatively spared, type II lissencephaly is frequently associated with other CNS malformations. Most common are the Dandy-Walker malformation and cerebellar cortical dysplasia. The diffuse, thick nature of the pachygyria/lissencephaly malformation suggests a failure of neurons to migrate completely through the developing white matter. Similar assumptions can be made about cerebral heterotopia, where groups of neurons fail to migrate fully

Figure 28-6 Polymicrogyria. The border of polymicrogyria and normal cortex. The border is extremely well delineated. The polymicrogyria is characterized by fusion of layer I, continuity of layer IV, and extensive undulating folds of cerebral cortex.

to their cortical destination, remaining in the developing white matter or periventricularly. Thus, the pathogenesis of these malformations is believed to be early in cortical neurogenesis, probably beginning around 10 to 12 weeks of gestation or earlier.

Polymicrogyria is frequently recognized as a fine stubbling on the surface of the brain (described as similar to Morroccan leather in appearance). By MRI and gross examination of brain sections, the cerebral cortex shows a complex set of small gyri that appear fused to each other. Microscopic examination confirms the gross impression, highlighting the small, complex gyri and fusion of layer 1 ( Fig,..2.8:6 ). Controversy exists as to whether polymicrogyria is a malformation or a disruption of development. The answer is likely to be both. Given that polymicrogyria is almost always present at the margins of disruptions, such as porencephaly, and in the setting of malformations, such as Zellweger's syndrome and triploidy, the conclusion often drawn is that there are multiple pathogeneses for polymicrogyria. Unfortunately, some overlap exists in the microscopic features of polymicrogyria regardless of the presumed pathogenesis. However, unlike lissencephaly and pachygyria, the border between polymicrogyria and normal cortex is distinct, and layer 6 in adjacent normal cortex and the deepest layers of the malformed polymicrogyric cortex are contiguous (see Fig 28-6 ). Based on the pathological features of polymicrogyria, the timing is later in neocortical development, generally believed to arise from defects occurring between 17 to 18 weeks' and 24 to 26 weeks' gestation.

Cerebral heterotopia are collections of disorganized gray matter in inappropriate places (...Fig 28-7. ). Heterotopia in the cerebral hemispheres can take on one of many patterns. They may occur as focal, isolated anomalies found incidentally on imaging or at autopsy, or they may have clinical manifestations, as described later. Occasionally, an isolated heterotopia or multifocal cerebral heterotopia are associated with an overlying cortical malformation. Another pattern is that of bilateral subcortical heterotopia, which may

Figure 28-7 Periventricular nodular heterotopic^, An MRI from a patient with extensive periventricular heterotopia, Courtesy of Dr. C. Walsh.) The heterotopia are the same signal intensity as the cerebral cortex and scallop the margin of the ventricular surface. Histological sections from a normal fetu;(B) at 20 weeks' gestation and a similar age fetus with periventricular heterotop^). The germinal tissue normally present around the angle of the lateral ventricle is replaced by several nodules of maturing grey matter (heterotopia).

be strikingly symmetrical. Islands of subcortical laminar heterotopia separated from the malformed cortex by a band of white matter create the entity known as double cortex. In addition to white matter heterotopia, glial and neuroglial heterotopia are often found in the leptomeninges overlying a cortical anomaly or around the base of the brain. The displaced tissue can form a radiographically and grossly identifiable plaque over the surface of the brain.

Another group of anomalies of cerebral cortical development that is being recognized with increasing frequency are the focal cortical dysplasias or cortical migrational anomalies(.Fig 28-8 ). The increasing practice of surgery in the management of intractable seizures has resulted in the recognition of a variety of cortical malformations in a significant number of cases.y Although polymicrogyria and pachygyria have been seen in many cases, the most frequent anomaly has been labeled focal cortical dysplasia. This disorder is characterized by a disruption in the lamination pattern, and by maloriented neurons in inappropriate layers including layer 1 and in the cerebral white matter. Their pathogenesis is unclear.

Epidemiology and Risk Factors. The incidence of disorders resulting from neuronal migrational abnormalities is unknown. Most of the cortical migrational disorders, particularly the diffuse ones, show a variety of inheritance patterns. Other cases show no clear inheritance and appear to be sporadic. A variety of environmental risk factors, including retinoic acid, methylmercury, and radiation, have been associated with the development of neuronal migrational disorders. In utero infections, particularly viral, are also known to result in cortical migrational abnormalities. The pathogenesis for viral induced migrational disorders remains unknown, although a destructive process is speculated to underlie the defect.

Clinical Features and Associated Disorders. The most striking clinical context in which type I lissencephaly is seen is the Miller-Dieker syndrome. Classic facial features include bitemporal hollowing, a rather short nose with a broad bridge and upturned nares, long and thin upper lip, small chin, and mildly low-set and posteriorly rotated ears. Although this constellation is referred to as the Miller-Dieker facial dysmorphism, the findings can be rather subtle. Most individuals with type I lissencephaly present in the neonatal period with marked hypotonia.

Figure 28-8 Focal cortical dysplasia. An axial MRI scan from a patient with focal cortical dysplasia. The left hemisphere shows a normal cortical ribbon; however, in the right hemisphere, in the posterior frontal lobe the cortical ribbon is abnormally thickened and the sulcal pattern is lost. The underlying white matter may be slightly th(Courtesy of Dr. R. Robertson.)

Later, a spastic quadriparesis dominates the picture. Seizures are a constant part of the clinical picture; they can start as neonatal seizures but more commonly present as infantile spasms with myoclonic and tonic seizures that later lead to Lennox-Gastaut syndrome with the additional occurrence of atonic seizures. The electroencephalogram typically shows fast alpha- and beta-activity admixed with high-amplitude slow activity. Mental and psychomotor retardation are usually profound. Cardiac anomalies occur in 20 to 25 percent of patients, and there can be genital anomalies in about 70 percent of males.

Type II lissencephaly occurs in a group of disorders associated with congenital muscular dystrophy, often involving the eyes as well. The Walker-Warburg syndrome, the Finnish muscle-eye-brain disease (MEB), and Fukuyama congenital muscular dystrophy (FCMD) are entities within this group. The Walker-Warburg syndrome (WWS) is the most severe of these, and the syndrome has a high proportion of neonatal lethality. The brain malformation often is complex with hydrocephalus, cerebellar hypoplasia (and occasionally Dandy-Walker malformation), and sometimes an occipital encephalocele associated with the cortical malformation. Clinically, it is characterized by profound hypotonia in the neonatal period due to the combined muscle and CNS involvement. The eyes can be affected in a number of ways, of which retinal dysplasia is the most consistent. Anterior chamber malformations, cataracts, choroidal colobomata, optic nerve hypoplasia, and microphthalmia can occur. Serum creatine kinase levels are elevated. Arthrogryposis may be present, and contractures may develop later. This condition is inherited in an autosomal recessive fashion, and as yet, no gene or genetic localization has been defined.

MEB of Santavouri has many features that resemble WWS; the disorder is prevalent predominantly in Finland. y This condition presents at birth or the first few months of life with hypotonia and weakness. Serum CK levels are consistently elevated after 1 year of age and often earlier. Subsequent psychomotor development is markedly delayed; however, many patients will acquire the ability to stand and walk. Mental retardation and seizures are common. The EEG is usually abnormal and progressively so after about 6 to 7 years of age. Most patients show a progressive motor deterioration, increasing spasticity, and contractures by 5 years of age. The eye abnormalities consist of high myopia, retinal degeneration, and optic atrophy. Congenital glaucoma and juvenile cataracts may also be present. The visual evoked potentials tend to be progressively delayed and of abnormally high amplitude, with an abolished electroretinogram at the same time. Neuroimaging often reveals less severe but comparable findings of MEB syndrome to WWS. Hydrocephalus is seen frequently, and patchy white matter abnormalities can be seen on T2-weighted MRI images.

FCMD is the second most common muscular dystrophy in Japan;y only Duchenne muscular dystrophy is identified more frequently. It appears to be extremely rare outside of Japan. In contrast to the MEB and WWS, eye involvement is generally less frequent and less severe. Patients show considerable psychomotor retardation and progressive muscular weakness and contractures. Seizures occur in about 50 percent of patients. When present, ocular findings include myopia and optic atrophy. MRI of the brain demonstrates the areas of pachygyria as well as polymicrogyria. Areas of abnormal T2 signal on MRI can be seen in the white matter. The cerebellum is only mildly affected, and hydrocephalus is rare. Linkage to chromosome 9q31 has been established for this autosomal recessive disorder; however, at the time of writing, the responsible gene had not been isolated.

Polymicrogyria has a less heterogenous clinical presentation than does lissencephaly. For all practical purposes, the different forms of polymicrogyria, independent of their syndromic or etiological context, present with often focal seizures. The various syndromic associations of polymicrogyria are discussed later under differential diagnosis.

Heterotopia can be sporadic, inherited as a simple Mendelian trait, or be part of a more complex syndrome. When heterotopia appears in isolation, the main presenting feature is seizures of various kinds, although by no means are they obligatory. Onset of the seizures can be from childhood (most commonly) to adulthood. Focal, multifocal, and generalized seizures can occur. Infantile spasms and the Lennox-Gastaut syndrome are seen at the severe end of that spectrum. Other neurological problems such as motor impairments and mental retardation may co-exist. The risk for these additional manifestations is lowest when the abnormality is localized to the periventricular region, higher in white matter heterotopia, and highest in diffuse subcortical band heterotopia. However, even in diffuse subcortical band heterotopia, normal psychomotor development can be seen, although it is infrequent.

The initial presentation of cortical dysplasia is most commonly the onset of various types of seizures. With this presentation, there are no clear signs or symptoms that predict cortical dysplasia versus another cortical lesion. The age of seizure onset tends to be in childhood, but can be delayed into adulthood and can be as early as infancy.[51] When the condition appears in infancy, the clinical picture can vary from clearly focal-appearing seizures to infantile spasm with relatively minimal or no focal clinical features. Later, the seizures may also include tonic seizures as well as drop attacks. Onset during the first few days of life as an Early Infantile Epileptic Encephalopathy (EIEE) has also been described. y EEG findings can be variable. y , y

Differential Diagnosis. Among the conditions with lissencephaly type I, the Miller-Dieker phenotype is distinguished from the isolated lissencephaly sequence (ILS) by the lack of distinctive facial features in ILS. However, bitemporal hollowing and a small chin can be seen in ILS as well. Furthermore, FISH analysis has demonstrated 17p13.3 microdeletions in a significant number of ILS cases. y However, other probes appear to distinguish between the two entities, suggesting a difference in the physical extent of the deletions, potentially accounting for the additional anomalies in the Miller-Dieker syndrome like the loss of contiguous genes. Other cases of ILS could possibly result from mutations in other genes.

The differential diagnosis of the lissencephaly II syndromes can be difficult. These difficulties are reflected in the many essentially synonymous designations of these syndromes, including the MEB syndrome; hydrocephalus, agyria, retinal dysplasia, ± encephalocele (HARD±E); and congenital ocular aysplasia/muscular dystrophy

(CODM) syndromes. Although there is no difference in principle between WWS and MEB syndromes beyond the degree of severity, this does not automatically prove that they are allelic variants at the same gene locus. The short survival of the WWS patients does not allow for a careful longitudinal analysis of the kind that has been conducted in MEB patients, potentially obscuring clinically relevant differences. Clearly, this question awaits the genetic assignment of both phenotypes. However, it now appears clear that MEB disease is genetically distinct from the related FCMd. FCMD maps to chromosome 9q, from which MEB has been excluded. Fukuyama muscular dystrophy, despite many similar features, usually does not include the severe eye and brain anomalies found in the WWS.

Many other syndromes and associations may show variable forms of lissencephaly, pachygyria, and polymicrogyria as features and many cases are not easily classified into any particular syndrome ( Table,.28:2 ). '55] Discussions of these rare disorders have been reviewed. y A number of metabolic conditions can also be associated with pachygyria and lissencephaly. The most frequent syndrome to show such an association (along with polymicrogyria) is Zellweger's syndrome. y This is a disorder of peroxisomal biogenesis that is characterized by marked neonatal hypotonia, facial dysmorphism, wide open fontanelles, and renal and hepatic abnormalities. Neonatal adrenoleukodystrophy and bifunctional enzyme deficiency are also peroxisomal disorders that may show migrational abnormalities. Glutaricaciduria type II, pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, and sulfite oxidase deficiency/molybdenum co-factor deficiency are examples of other metabolic disorders that occasionally include a cortical dysplastic malformation as one of the manifesting features.

The differential diagnosis of conditions with polymicrogyria also is rather extensive, y reflecting the nonspecific nature of the malformation. In addition to the lissencephaly type II conditions discussed already, Aicardi's, Neu-Laxova, Zellweger's, and Smith-Lemli-Opitz syndromes could be mentioned as monogenic conditions. Polymicrogyria can also occur with a variety of chromosomal abnormalities. As outlined earlier, disruptive and destructive disorders can have polymicrogyria associated with them. The most common association is with congenital cytomegalovirus infection, and the timing of this malformation is probably similar to the disruptions of porencephaly and hydranencephaly. In fact, both of these disorders have been reported with congenital cytomegalovirus infection, as well as other congenital infections. Extensively fused polymicrogyria can be difficult to differentiate from pachygyria on imaging.

Periventricular as well as subcortical band heterotopia can occur as X-linked inherited conditions, mapping to different regions on the X chromosome. y In familial band heterotopia, affected females present with the heterotopia and often seizures, whereas affected males show more severe brain malformations, including lissencephaly. This factor may be due to random X-inactivation in females preventing full expression of the defect, and it also raises the possibility that a spectrum of developmental disturbances, from focal heterotopia to lissencephaly, exists with a common pathogenesis. y , y , y In X-linked familial periventricular heterotopia, affected male family members also have a more severe malformation and clinical phenotype than affected female siblings. y Again, a number of syndromes include neuronal heterotopia with some regularity. For example, in Aicardi's syndrome, heterotopias are as constant a feature as agenesis or hypoplasia of the corpus callosum. Retinal lacunae, cerebellar abnormalities, and hemivertebrae may also be found in this syndrome. Aicardi's syndrome is probably an X-linked dominant male lethal condition, so that only girls are affected clinically. The presentation is with severe early seizures (infantile spasms) and profound psychomotor retardation. An interesting addition to the list of metabolic conditions associated with heterotopia, in which the peroxisomal disorders again are represented, is the Smith-Lemli-Opitz syndrome (type II), diagnosed by an elevated level of plasma 7-dehydrocholesterol.

The differential diagnosis of polymicrogyria versus focal cortical dysplasia can be difficult because of the similar clinical presentation with focal seizures. Imaging is the instrument that is most often used to differentiate the two (see later). The so-called benign focal epilepsies of childhood are important to differentiate from fixed cortical malformations, because their prognosis and management are different.

Evaluation. The diagnosis of the Miller-Dieker syndrome and also the isolated lissencephaly sequence is based on the finding of a smooth brain surface with widely open sylvian fissures on neuroimaging studies, an appearance that has been called the figure8 sign. The broad cortex in relation to the extremely narrow white matter can be seen on MRI. Cytogenetically visible deletions of the critical chromosomal region 17p13.3 are seen in about two thirds of clinically convincing cases. y More then 90 percent of

TABLE 28-2

-- SUMMARY OF MAJOR SYNDROMES WITH CORTICAL MALFORMAT

ONS

Disorder

Cerebrum

Cerebellum

Hydrocephalus

Eye

Muscle

Other

MDS

A

-

-

-

-

-

ILS

A

-

-

-

-

-

WWS

A, P, E

DWS

+

+

+

+

MEB

A, P, E

DWS

+

+

+

-

Fukuyama

A, P

-

+/-

+/-

+

-

NL

A, P

+

-

+

-

+

Zellweger's

A, P

+

-

-

-

+

NRS

A

+

-

-

-

-

MDS, Miller-Dicker syndrome; ILS, isolated lissencephaly sequence; WWS, Walker-Warburg syndrome; MEB, muscle-eye-brain disease; NL, Neu Laxova syndrome; NRS, Norman-Roberts syndrome; DWS, Dandy-Walker malformation; A, agyria; P, pachygyria; E, encephalocele; +, affected; -, unaffected.

MDS, Miller-Dicker syndrome; ILS, isolated lissencephaly sequence; WWS, Walker-Warburg syndrome; MEB, muscle-eye-brain disease; NL, Neu Laxova syndrome; NRS, Norman-Roberts syndrome; DWS, Dandy-Walker malformation; A, agyria; P, pachygyria; E, encephalocele; +, affected; -, unaffected.

patients show loss of this critical region when FISH analysis is employed.

Type II lissencephaly has an appreciably different MRI appearance, with a gray to white matter ratio of 1:1. Here, as well as for all of the other disorders of neuronal migration, careful evaluation of the morphology of the cortex by MRI is essential. In cases of type II lissencephaly/pachygyria, especially in the presence of associated CNS malformations or abnormalities of the eyes, the congenital muscular dystrophies with associated eye abnormalities have to be considered. Determination of serum creatinine kinase levels, and muscle biopsy may become necessary. Once the diagnosis of a congenital muscular dystrophy with structural brain abnormalities has been made, the differential diagnosis between the individual conditions should follow the considerations outlined earlier. Prenatal diagnosis of WWS by ultrasound is possible, although not always easy. The posterior fossa anomalies and demonstration of retinal detachment are helpful.

The workup for focal cortical abnormalities of migration also relies heavily on extremely high-quality MRI, because some of these lesions can be very hard to detect. Clinical suspicion must remain high and hints, such as delayed myelination underneath a cortical region, may be valuable in defining the location of the abnormality. The value of functional imaging techniques such as positron-emission tomography, single photon emission computed tomography, and perfusion-diffusion MRI at this point cannot be generalized. These techniques are under active development. Several special MRI techniques, such as three-dimensional surface rendering, are also being evaluated for this purpose and appear promising. At a minimum, high-resolution imaging with thin cuts and optimal gray to white matter resolution for the age of the patient is essential. On EEG, focal very high amplitude rhythmical activity is characteristic of cortical dysplasias; however, this activity is recorded in less than half of the cases. Other EEG patterns, such as focal abnormal fast activity, have no predictive value for a focal dysplasia. At times, the surface EEG can be normal or appear to show primary generalized spike and wave discharges. An additional diagnostic problem is the question of whether the underlying lesion is unifocal or multifocal. Multifocal discharges on the EEG do not necessarily mean multifocality of the dysplasias, although they can. Conversely, electrographical evidence for only one focus does not exclude the existence of additional foci. Long- term video-telemetry monitoring may be helpful in evaluating these questions. In cases in which seizures are resistant to medical management and there is a high degree of suspicion for a focal cortical abnormality but lack of noninvasive evidence, intraoperative electrophysiology may prove useful. Resected pathological material often shows features of cortical dysplasia.

Management and Prognosis. In general, the prognosis for patients with Miller-Dieker syndrome and WWS is very poor, and many patients do not survive infancy. Very little psychomotor development, if any, takes place. Insertion of a gastric tube may be necessary to provide adequate nutrition, prevent aspiration, and facilitate care. Treatment of the often prominent seizures follows general guidelines.

In the congenital muscular dystrophies with structural brain abnormalities, the brain malformation may require surgical intervention for the hydrocephalus or sometimes for the encephalocele in WWS. If the hydrocephalus is due to aqueductal stenosis and a Dandy-Walker anomaly is present, shunting of both the lateral ventricles and the posterior fossa cyst may become necessary. The prognosis is better in the Finnish MEB disease, and although patients often acquire the ability to walk, there may be secondary deterioration because of increasing spasticity. In this condition, ophthalmological management becomes important: high myopia, cataracts, glaucoma, and retinal detachment may require intervention.

The epileptic syndrome in migrational abnormalities is often medically intractable, surgical extirpation of the lesion is often desirable, and earlier surgical intervention may improve the overall developmental prognosis. For an isolated focus of polymicrogyria or cortical dysplasia presenting with intractable seizures, extirpation can be curative; however, multifocality is not an automatic contraindication against the surgery, because extirpation of a major focus may result in overall improvement of seizure control. The presurgical and intraoperative evaluation is essential for success of the surgery and is dealt with in detail in reference 60. For isolated epileptogenic heterotopias, surgical excision also is an option; the drop attacks that can be seen in the diffuse bilateral band heterotopias may respond to callosotomy.y

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