Dr. Vrajesh Udani*
Consultant Child Neurologist, PD Hinduja National Hospital, Mumbai
Email: firstname.lastname@example.org *
Genetic malformations of the cerebral cortex are usually characterized by malposition and faulty differentiation of grey matter. Epilepsy is often present and tends to be severe, although its incidence and type vary in different malformations.
It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation.
Disorders affecting neuronal migration are characterized by abnormal neuronal positioning.
|MALFORMATIONS RELATED TO ABNORMAL PROLIFERATION OF NEURONS AND GLIA |
In Hemi-megalencephaly, one cerebral hemisphere is enlarged and presents with a thick cortex, wide convolutions, and reduced sulci. Laminar organization of the cortex is absent, and grey-white matter demarcation is poor. Giant neurons are observed throughout the cortex and the underlying white matter. In about 50% of cases, large, bizarre cells are observed, which have been named balloon cells. Localization and the fact that the malformation has always been sporadic can indicate somatic mosaicism.
Hemimegalencephaly has been described in the context of different, disorders, including epidermal nevus syndrome, Proteus syndrome, hypomelanosis of Ito, neurofibromatosis type 1, and tuberous sclerosis, but occurs most frequently as an isolated malformation. The clinical and anatomic spectrum of severity is wide, ranging from severe epileptic encephalopathy beginning in the neonatal period of patients with normal cognitive function. Indeed, the milder end of the clinical spectrum includes patients with well-controlled seizures or no seizures at all. However, most patients have a severe structural abnormality and almost continuous seizures. The most common presentation is asymmetric macrocrania, hemiparesis, hemianopia, mental retardation, and seizures. The electroclinical features usually include partial motor seizures beginning in the neonatal period, infantile spasms, and often an symmetric suppression-burst pattern on sleep electroencephalography (EEG). Patients with early-onset, severe epilepsy almost always develop major cognitive and motor impairment. In addition, there is high mortality rate in the first months or years of life, with status epilepticus being the most important cause of death. Hemispherectomy is the only effective treatment when the epilepsy is severe and intractable. There are indications that if surgery is performed, it should be performed early because in younger children, transfer of functions to the "normal" hemisphere is greater and a better neuropsychologic outcome is more likely.
Focal cortical dysplasia
Focal cortical dysplasia was originally described in patients who were treated surgically for drug-resistant epilepsy. The histologic abnormalities include local disorganization of the laminar structure, large aberrant neurons, isolated neuronal heterotopia in subcortical white matter, balloon cells, giant macroglia, foci of demyelination, and gliosis of adjacent white matter. The abnormal area is not usually sharply demarcated from adjacent tissue. Three main subtypes of focal cortical dysplasia are recognized, which might correspond to the different times of embryologic origin. A first type is characterized by architectural dysplasia, with abnormal cortical lamination and ectopic neurons in the white matter. A second type, defined as cytoarchitectural dysplasia, is characterized by giant neurofilament-enriched neurons in addition to altered cortical lamination. A third type, corresponding to Taylor-type cortical dysplasia, is characterized by giant dysmorphic neurons and balloon cells associated with cortical laminar disruption. Magnetic resonance imaging (MRI) can be unrevealing in up to 34% of patients especially in the first two types. Distinctive signal alterations on T2 weighted or fluid-attenuated inversion recovery images are present in most patients with Taylor-type dysplasia, often associated with focal areas of cortical thickening, simplified gyration, blurring of the grey-white limit, or rectilinear boundaries between grey and white matter.
Focal cortical dysplasia usually presents with intractable focal epilepsy, which can start at any age but generally before the end of adolescence. Seizure semiology depends on the location of the lesion, and focal status epilepticus had been reported frequently. Unless the dysplastic area is large, patients do not suffer from severe neurologic deficits. The ictal EEG abnormalities are highly specific for focal cortical dysplasia, are located over the epileptogenic area, and correlate with the continuous epileptiform discharges recorded during electrocorticography.
The interictal EEG shows focal, often rhythmic epileptiform discharges in about half of the patients. Most patients with electrocorticographic ictal discharges who had complete removal of the discharging tissue were seizure free or had over 90% reduction in major seizures. None of the patients with persistence of discharging tissue had a favorable outcome. Patients with Taylor-type dysplasia had the best outcome with 75% being seizure free (Engel class 1a) compared with 50% with cytoarchitectural dysplasia and 53% with architectural dysplasia.
|MALFORMATIONS OWING TO ABNORMAL NEURONAL MIGRATION |
Periventricular Nodular Heterotopia
Periventricular nodular heterotopia, often bilateral, consists of confluent nodules of grey matter located along the lateral ventricles. Although most patients with periventricular nodular heterotopia are brought to medical attention because they have epileptic seizures without additional neurologic abnormalities, the spectrum of clinical presentations is wide.
Periventricular nodular heterotopia occurs much more frequently in women as X-linked bilateral periventricular nodular heterotopia. About 20% of sporadic patients (19% of sporadic women and 9% of sporadic men) harbor mutations of the filamin 1 gene (FLN1).
Heterozygous females have normal to borderline intelligence and epilepsy of variable severity.
Genetic counseling is relatively easy in familial cases with a clear X-linked pattern of inheritance. Classic periventricular nodular heterotopia with cerebellar hypoplasia and no dysmorphic features is much more frequent in women and more likely to be due to FLN1 mutations than is the case in atypical cases.
Approximately 90% of patients with periventricular nodular heterotopia have epilepsy, with periventricular nodular heterotopia have epilepsy, which can begin at any age. Surgical removal of the heterotopic cortex, as well as the normal-appearing epileptogenic cortex, led to seizure freedom.
Classic Lissencephaly and Subcortical Band Heterotopia (Agyria-Pachygyria-Band Spectrum). Lissencephaly (smooth brain) in characterized by absent (agyria) or decreased (pachygyria) convolutions, producing a smooth cerebral surface. The most frequent forms are caused by mutations of the LIS1 gene. Subcortical band heterotopia is a slightly different malformation that is now included within the agyria pachygyria-band heterotopia spectrum. In subcortical band heterotopia the cortex is simplified with broad convolutions and increased cortical thickness. Just beneath the cortical ribbon, a thin band of white matter separates the cortex from a heterotopic band of grey matter of variable thickness and extension. Most cases of subcortical band heterotopia are caused by mutations of the DCX gene and a minority by mutations of the LIS1 gene.
Lissencephaly (smooth brain) in characterized by absent (agyria) or decreased (pachygyria) convolutions, producing a smooth cerebral surface. The most frequent forms are caused by mutations of the LIS1 gene.
A morphologic feature that is common to the malformative spectrum caused by LIS1 mutations is a posteriorly predominant brain abnormality. The LIS1 is the gene responsible for all cases of Miller-Dieker lissencephaly, which is caused by large deletions of LIS1 and contiguous genes, for approximately 65% of isolated lissencephaly cases and in almost all those in which the gyral disorder is more severe posteriorly.
DCX mutations usually cause classic lissencephaly in hemizygous males and subcortical band heterotopia in heterozygous females. All female pair with DCX mutations and abnormal MRIs have an anteriorly predominant band or pachygyria.
All female pair with DCX mutations and abnormal MRIs have an anteriorly predominant band or pachygyria.
Classic Lissencephaly has a prevalence of 11.7 per million births (1 in 85,470). Affected children have been early developmental delay and eventual profound mental retardation and spastic quadriparesis. Some children with severe lissencephaly have lived more than 20 years, but their life span is often shorter. Seizures occur in over 90% of children, with onset before 6 months in about 75%. About 80% have infantile spasms, although the EEG might not show typical hypsarrhythmia. Most children subsequently have multiple seizure, including persisting spasms, focal seizures, tonic seizures, atypical absences, and atonic seizures. The EEG demonstrates diffuse, high-amplitude, fast rhythms, which are considered to be highly specific for this malformation.
The main clinical manifestations of subcortical band heterotopia are mental retardation and epilepsy. Cognitive function ranges from normal to severe retardation and correlates with the thickness of the band and the degree of pachygyria. Epilepsy is present in almost all patients with subcortical band heterotopia and is intractable in about 65%.
Laboratory Testing Strategy in Lissencephaly
When Miller-Dierker syndrome is suspected, a standard chromosome analysis and fluorescent in situ hybridization assay (FISH) on chromosome 17p13.3 are indicated. If both tests are normal, the patient is very likely not to be affected with Miller-Dieker syndrome. When non syndromic isolated lissencephaly is diagnosed, careful assessment of the anteroposterior gradient of gyral pattern abnormality and cortical thickness will be suggestive of the involvement of either the LIS1 or the DCX gene. When lissencephaly is more severe posteriorly, it is worth performing the chromosome analysis with a fluorescent in situ hybridization assay on chromosome 17p13.3. If a deletion is not found, LIS1 gene sequencing and the Southern blot analysis should be performed consequently. In boys whose MRI shows more severe pachygyria in the frontal lobes, sequencing of the DCX gene is indicated.
When lissencephaly is more severe posteriorly, it is worth performing the chromosome analysis with a fluorescent in situ hybridization assay on chromosome 17p13.3. If a deletion is not found, LIS1 gene sequencing and the Southern blot analysis should be performed consequently.
|MALFORMATIONS OWING TO ABNORMAL CORTICAL ORGANIZATION|
Schizencephaly (cleft brain) consists of a unilateral or bilateral full thickness cleft of the cerebral hemispheres with communication between the ventricle and extra-axial subarachnoid spaces. The clefts are most often found in the perisylvian area. Because the cortex surrounding the cleft of the fissure is polymicrogyric, schizencephaly is considered a disorder of cortical organization.
Septo-optic dysplasia (agenesis of the septum pellucidum and optic nerve hypoplasia) is seen in up to one third of patients. Local failure of induction of neuronal migration or focal ischemic necrosis with destruction of the radial glial fibers during early gestation has been hypothesized. Schizencephaly is usually sporadic.
Clinical findings include focal seizures in most patients (about 80% of cases in one large review), usually beginning before age 3 years in bilateral cases. Bilateral clefts are associated with microcephaly, severe delay, and spastic quadriparesis, whereas patients with unilateral schizencephaly most often have hemiparesis or can be brought to medical attention after seizure onset without having any other neurologic abnormality.
Bilateral clefts are associated with microcephaly, severe delay, and spastic quadriparesis, whereas patients with unilateral schizencephaly most often have hemiparesis or can be brought to medical attention after seizure onset without having any other neurologic abnormality.
Polymicrogyria is characterized by an excessive number of small and prominent convolutions spaced out by shallow and enlarged sulci, giving the cortical surface a lumpy appearance. Cortical infolding and secondary irregular thickening owning to packing of microgyri are visible on MRI although mild forms are difficult to recognize on neuroimaging.
The extent of polymicrogyria varies greatly and there is a broad range of clinical manifestations, from severe encephalopathy with intractable epilepsy to individuals with only selective impairment of cognitive functions.
Bilateral perisylvian polymicrogyria involves the grey matter bordering the sylvian fissure bilaterally. Both four-layered polymicrogyria and unlayered polymicrogyria have been observed.
Although most patients are sporadic, several familial cases have been reported, with possible autosomal recessive, autosomal dominant, X-linked dominant, and X-linked recessive inheritance.
Affected patients have faciopharingo-glosso-masticatory diplegia and dysarthria. Most have mental retardation and epilepsy. Those with more extensive damage can be spastic quadriparetic. Seizures usually begin between age 4 and 12 years and are poorly controlled in about 65% of patients. The most frequent seizure types are atypical absence seizures, tonic seizures, atonic drop attacks and tonic-clonic seizures, often occurring as LGS-like syndromes. A minority of patients (about 25%) have focal seizures only, predominantly involving the perioral or facial muscles. Infantile spasms have also been reported in a minority of patients. Patients with tonic or atonic seizures causing disabling drop attack can be amenable to anterior callosotomy, with fairly good results. Lateralization of seemingly generalized seizures has been clearly documented after callosotomy in bilateral perisylvian polymicrogyria.
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