Bilateral frontal polymicrogyria

Methods and patients.

The patients were studied at four different institutions between 1990 and 1997, often following referral from other centers. MRI was performed between the ages of 10 months and 32 years, using 0.5-tesla or 1.5-tesla scanners, during investigations for developmental delay, mental retardation, hemiparesis or quadriparesis, seizures, or a combination of these abnormalities. Only two patients (Patients 7 and 11) had previously had a brain CT scan, which showed irregular BFP thickening. Noncontrast spin-echo, inversion recovery (IR), and gradient-echo MRI sequences were performed in the axial, sagittal, and coronal planes. Nine patients were studied with standard 5-mm slice thickness and four were studied by using three-dimensional Fourier transform gradient-echo technique with gradient spoilers, allowing partition size of 1.5 mm and reformatting of images in any plane. Measurement of the cortical thickness was made by using calipers on the hard copy of the films.

All patients had medical and neurologic examinations. Their cognitive level was assessed using one of the Wechsler intelligence scales or adaptive behavioral criteria8 and classified as mild, moderate, or severe according to standard criteria. The five patients with epilepsy underwent EEG recordings using the 10-20 International Electrode Placement System. Epileptic seizures were classified according to the recommendations of the International League Against Epilepsy.9 Data for postnatal Toxoplasma, rubella, cytomegalovirus, and herpesvirus (TORCH) screening were available for five patients (9 to 13). Chromosome analysis on blood lymphocytes was performed in all patients.

Results.

The clinical abnormalities are summarized in the table. Family history was significant for parental consanguinity in two families in which the parents were first cousins (Patients 10 and 13), but no other relatives were recognized to be affected. All pregnancies were reportedly uneventful, with the exception of Patients 11’s mother, who had a prolonged respiratory viral illness from 4 to 8 months of pregnancy. Labor and delivery were normal and full term for all patients, with the exception of Patient 12, who was born by Cesarean section.

Delayed motor milestones with axial hypotonia were reported early in life and motor signs were present in all patients, varying from symmetric spastic quadriparesis in 10 patients to double hemiparesis in 3 patients. Four of the five patients older than 3 years of age were able to walk independently despite the spasticity. None of the eight patients 3 years of age or younger had acquired independent walking. Mental retardation varied from mild to moderate. Development of language was severely impaired. The three infants younger than 2 years of age had delayed preverbal skills. Speech was still absent in five of the six children aged 2 to 6 years. All four patients older than 6 years of age had poorly developed language skills. Comprehension of language was more advanced than expressive speech. No signs of bulbar paralysis were present, although two patients (Patients 8 and 11) had persistent drooling. Head circumference was normal in all but one patient (Patient 12).

MRI showed irregular infoldings of the cerebral surface with abnormally thick 5- to 7-mm cortex involving the frontal lobes bilaterally, compared with normal MR values of 3 to 4 mm.10 The abnormal cortex extended from the frontal poles anteriorly to the precentral gyrus posteriorly and to the frontal operculum inferiorly and was relatively symmetric in all patients (figure, A through C). The perisylvian cortex was spared, showing neither cortical thickening nor abnormal orientation of the sylvian fissure. Close examination of the malformed cortex showed that it was composed of multiple small fused gyri, with irregular interdigitations at the gray–white junction, an appearance characteristic of polymicrogyria11 (figure, A through C). The volume of the underlying white matter appeared mildly reduced, and the overlying subarachnoid space was mildly enlarged. Associated abnormalities included multiple, small foci of T₂ hyperintensity in the frontal white matter in three patients (Patients 1, 2, and 4), mild thinning of the corpus callosum involving either the body or the splenium in four patients (Patients 1, 2, 4, and 5), and mild ventriculomegaly in six patients (Patients 1, 4, 5, 6, 8, and 9). The remainder of the cerebral cortex, brainstem, and cerebellum appeared normal in all patients.

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Figure. Sagittal inversion recovery weighted (A) and T₁-weighted (B) images of Patients 7 (A) and 8 (B) showing thickened cortex with irregularity of the cortical–white matter junction involving the frontal lobe. Axial T₁-weighted (C) image of Patient 8 showing that the dysplastic, presumably polymicrogyric cortex (arrows) extends posteriorly to the precentral gyri. Schematic (D) showing distributions of bilateral symmetric polymicrogyria. Small, dark dots on light background represent distribution of bilateral frontal polymicrogyria. Large, dark dots on light background represent distribution of bilateral perisylvian polymicrogyria. Small, light dots on dark background represent distribution of parasagittal parieto-occipital polymicrogyria.

The interictal EEG recordings performed in the five patients with epilepsy showed bilateral frontal slowing of background activity with superimposed sharp waves and spike-and-wave activity associated with diffuse abnormalities. One of these patients (Patient 7) had poorly controlled complex partial and secondarily generalized seizures. The second patient (Patient 8) had partial motor seizures and atypical absences that were under control after having been drug resistant for several years. One patient (Patient 2) was studied soon after his first complex partial seizure and had no follow-up. The remaining two patients (Patients 11 and 13) were seizure free with medication.

Results of TORCH screening were normal in all 5 patients in whom this was performed. All 13 patients had a normal karyotype.

Discussion.

All 13 patients described in this article had a bilateral cortical malformation with an MRI appearance characteristic of polymicrogyria. The abnormal cortex involved nearly the entire frontal lobe bilaterally, extending from the frontal poles anteriorly to the precentral gyrus posteriorly, and to the frontal operculum inferiorly. The sylvian fissures appeared normal, including normal orientation.

BFP extends the spectrum of the recognized bilateral symmetric regional polymicrogyria syndromes affecting nonoverlapping areas of the cerebral cortex (figure, D). Topologic analysis of bilateral polymicrogyria12,13 suggests that certain cortical regions have a propensity to develop polymicrogyria. Moreover, it seems that well-defined boundaries exist and determine where the polymicrogyria seems to begin and end. One such boundary can be defined by a plane passing through the sylvian fissures (which are more vertical and posteriorly elongated when the perisylvian cortex is polymicrogyric) to the mesial parietal–occipital junction. Bilateral polymicrogyria has been described as involving only the anterior (perisylvian) portion of this plane,13 only the posterior (parieto-occipital) portion,12 or both.14 Bilateral frontal PMG involves the cortex anterior and superior to that plane.

Polymicrogyria is a developmental disorder characterized by abnormal arrangement of cell layers, excessive folding of layers, and fusion of the gyral surfaces.15 The abnormal convolutions are packed, merged, and abnormally folded, leading to the appearance of irregular cortical thickening on routine MRI sequences.11 Two types of polymicrogyria have been distinguished. Unlayered polymicrogyria is thought to result from either early exogenous insults (10th to 18th week of gestation)16,17 or to be genetically determined.18,19 Four-layered polymicrogyria is believed to arise between the 13th and 24th weeks of gestation, possibly caused by perfusion failure.19 The two types of polymicrogyria may co-occur in contiguous cortical areas,20 indicating that they may comprise a single spectrum rather than distinct malformations. Neuropathologic studies of syndromic regional polymicrogyrias are only available for sporadic cases with the bilateral perisylvian form; four-layered polymicrogyria was observed in three cases13,21 and unlayered polymicrogyria in one.22 In our patients with BFP, the lack of neuropathologic studies makes it impossible to establish which histologic type of polymicrogyria is present.

Polymicrogyria resulting from perfusion failure23-25 often is limited to the territory of a main artery or the watershed between major arterial territories.17,20,23 Several reported causes of polymicrogyria are thought to act through a final common pathway of perfusion failure,25 including infection fetopathies such as cytomegalovirus, maternal shock,26 or twin–twin transfusion syndrome.17,27,28 The mothers of our patients reported no evidence of significant prenatal events. Moreover, extensive bilateral frontal involvement is not compatible with any known vascular topography. Therefore, it seems unlikely that a prenatal vascular mechanism played a role in our patients.

The occurrence of BFP in two unrelated children born to consanguineous parents may be consistent with, although certainly not diagnostic of, autosomal-recessive inheritance. The same pattern of inheritance can be hypothesized for bilateral perisylvian polymicrogyria in two families with more than one affected sibling.13,29 However, bilateral perisylvian polymicrogyria has proved to be genetically heterogeneous, as examples of autosomal-dominant30 and X-linked30-32 inheritance have also been described, with X-linked inheritance the most common.

Analysis of genetically proven cases of polymicrogyria has shown significant phenotypic variability. In addition to the expected more-severe expression of the disorder in male individuals with an X-linked trait,31 high intrafamilial variability in the extent and symmetry of the cortical abnormality has been observed in individuals of the same sex.32,33 More extensive polymicrogyria extending to involve the frontal lobes has been observed in relatives of patients with more localized, usually perisylvian, polymicrogyria.32,34 It is therefore possible that distinct forms of regional polymicrogyrias may either result from abnormalities of several developmental genes with different area-specific expression35 or from variable topographic expression of the same gene or genes.

An attractive candidate gene for regional polymicrogyria is EMX2, a homeotic gene located on chromosome 10q26. This gene is mutated in some patients with schizencephaly,4 a malformation in which polymicrogyria covers unilateral or bilateral clefts36 that can be located anywhere in the brain. Unilateral clefts can be either isolated or associated with contralateral polymicrogyria.26 However, the search for EMX2 mutations in patients with bilateral perisylvian or parieto-occipital polymicrogyria has not yielded positive results (E. Boncinelli and R. Guerrini, unpublished data, 1998), and EMX2 mutations have not been reported from other centers.

The clinical manifestations associated with polymicrogyria show considerable diversity depending on the region and extent of the malformation. The manifestations range from severe encephalopathy to selective impairment of higher order neurologic functions in otherwise normal individuals.37,38 All of our patients with BFP presented with early developmental delay, variable mental retardation, and motor signs, which are well explained by extensive involvement of the frontal lobes, including the motor cortex. The malformation often was detected in early childhood, during investigations for delayed motor development, which may explain why only five patients had developed epilepsy. In contrast, when the motor cortex is unaffected and cognitive impairment is mild, such as in parieto-occipital polymicrogyria,12 the malformation usually is discovered at a much later age after onset of epileptic seizures. Although the clinical manifestations of our patients with BFP appeared consistent, they are not distinctive in that a similar clinical pattern may result from perinatal hypoxic-ischemic brain injury.39 Because of the wide age range of patients and the assessment in different institutions, we were unable to carry out neuropsychologic tests to determine whether selective frontal lobe dysfunction was present.