Polymicrogyria …

Harvey B Sarnat MD FRCPC MS

Developmental Malformations

Updated 08.05.2024
Released 01.19.1998
Expires For CME 08.05.2027

Polymicrogyria

Author: Harvey B Sarnat MD FRCPC MS

See Contributor Disclosures

Polymicrogyria

In This Article

Quick Link

Introduction

Overview

Polymicrogyria is a complex malformation of cortical development due to disorder of neuronal organization, in which the process of normal cerebral cortical development is disturbed in an early stage of cortical organization. Macroscopically or grossly, including by MRI, it is defined by clusters of gyri that are too small and too numerous for the area. Microscopically, not only are there numerous gyri in clusters but also many of the gyri are fused to adjacent gyri with continuity of their molecular zones and synaptic activity without the normal intervening subarachnoid space with leptomeninges and small meningeal blood vessels. Lamination of the cortex of these gyri is also abnormal with many displaced and disoriented neurons of all types, but there are no dysplastic megalocytic neurons as seen in focal cortical dysplasia type II, hemimegalencephaly, or tuberous sclerosis, except in some cases associated with a somatic mutation in the mTOR signaling pathway. Discontinuities or gaps in the pial membrane and lamina limitans, including the fetal subpial granular glial layer of Brun, are morphological features that lead to gyral fusion. Synaptic continuity of fused molecular zones (of mostly excitatory synapses) of adjacent microgyria results in epileptogenic short-circuitry. Clinical manifestations of perisylvian polymicrogyria include epilepsy, speech and language disturbance, and cognitive deficits, but polymicrogyria can be associated with many genetic syndromes with additional neurologic impairments; the spectrum of genes identified in polymicrogyria is very large, hence it is a heterogenous malformation.

Key points

	• Polymicrogyria is a cerebral malformation of cortical development with excessive folding of small, numerous fused gyri and normal or abnormal cortical lamination.
	• Fusion of gyri microscopically results in continuity of the molecular zone of adjacent small gyri without intervening pial membranes or leptomeninges; pathogenesis involves discontinuities in the pia of the cortex during gyration or sulcation after mid-gestation.
	• The underlying etiologies are multiple but can be summarized into three categories: (1) genetic disorders in which a wide range of unrelated mutations are reported; (2) association with other malformations of the brain, such as schizencephaly and cerebellar dysplasia, or with recognized genetic syndromes; and (3) vascular infarcts or ischemic zones, resulting in a wide variety of neurologic signs and symptoms.
	• The distribution of polymicrogyria most frequently is perisylvian; it always is associated with schizencephaly, but in other cases it may be focal in any lobe or can be generalized throughout the cortex of both hemispheres.
	• High-resolution MRI is the most reliable imaging modality for diagnosis and evaluating the distribution and extent of the dysgenesis and association with other brain malformations; fMRI shows decreased activation; neuropathology provides microscopic details not revealed by imaging. • The most constant clinical manifestations include epilepsy and sometimes even severe infantile epilepsies, cognitive impairment, and speech and language disturbance in perisylvian polymicrogyria. Many other findings in both brain and body occur with polymicrogyria in the various genetic syndromes.
	• Surgical resection of epileptogenic foci within polymicrogyria may provide good seizure control with better developmental outcome in children, but polymicrogyria is not always epileptogenic.
	• Neuroanatomical features at the single neuron level determine epileptic potential by shifting the excitatory/inhibitory ratio: short circuitry of the molecular zones of adjacent fused gyri, paucity of keratan sulfate inhibition of glutamatergic synapses, and clustering of Cajal-Retzius neurons that cause dyslamination of the cortical plate in microgyria. In cases due to an AKT family or other gene affecting the mTOR pathway, megalocytic dysplastic neurons and glial cells are found.

Historical note and terminology

Originally coined in the early 1900s by Bielschowsky (117), the term, “polymicrogyria” was largely replaced by the term “microgyria” by the middle of the 20th century. Contemporary preference has seen a resurgence of the term “polymicrogyria,” which more accurately describes the findings in this disorder (118).

Classification. Several types with various manifestations and etiologies have been noted. Under the current classification of malformations of cortical development, the following types of polymicrogyria are defined by MRI (11; 10). They also can be so classified by gross neuropathology.

(1) Bilateral frontal polymicrogyria (BFP)
(2) Bilateral frontoparietal polymicrogyria (BFPP)
(3) Bilateral perisylvian polymicrogyria (BPP)
(4) Bilateral parasagittal parieto-occipital polymicrogyria (BPPOP)
(5) Bilateral generalized polymicrogyria (BGP)
(6) Unilateral perisylvian polymicrogyria (UPP) (11)

Outdated names used for polymicrogyria include microgyria, micropolygyria, and status verrucosus deformis (38).

Clinical manifestations

Presentation and course

Polymicrogyria manifests as a spectrum of clinical signs and symptoms ranging from no manifestations to severe encephalopathy or cognitive impairment (73; 74). This disorder is associated with epilepsy in approximately 50% to 85% of patients (66; 71). Children often present with developmental delay, spasticity, or seizures; they are also often microcephalic. Some patients with polymicrogyria go undiagnosed until they have offspring with the disorder, who typically have more severe manifestations. Retrospectively, these patients will often report some difficulty in their medical or educational history (94).

The clinical presentation and course depend on localization and extent of the lesion, association with other brain malformations, and underlying genetic mutations or prenatally acquired lesions, but epilepsy and developmental delay are the most frequent symptoms in infancy. Seizure onset in the first year of life occurred in 44% in a Swedish study of 109 patients (88). Clinical diversity of polymicrogyria is largely determined by the extent of cortical involvement and localization of lesions with a topographic distribution of symptoms (73; 113).

(1) Frontal polymicrogyria typically have features of delayed motor and language milestones, spastic hemiparesis or quadriparesis, and mild to moderate mental retardation (28; 73).

(2) Bilateral frontoparietal polymicrogyria present with its most common symptoms of global developmental delay, dysconjugate gaze, pyramidal and cerebellar signs, and generalized seizures (28).

(3) Bilateral perisylvian polymicrogyria, the most frequent distribution, manifests as seizures that usually begin between 4 and 12 years of age as well as mental retardation, pyramidal signs, and pseudobulbar palsy that manifests as diplegia of the facial, pharyngeal, and masticatory muscles (facio-pharyngo-glosso-masticatory diplegia) (62). Dystonia occurs in some cases (05). Developmental delay may be observed, and malformations such as arthrogryposis (123), club feet, and micrognathia may be seen more commonly in the congenital form of the disorder. Perisylvian polymicrogyria is seen in all cases of schizencephaly, whether unilateral or bilateral. Some cases of bilateral perisylvian polymicrogyria also involve cerebellar dysplasia and ectopic neurohypophysis (161). Psychiatric symptoms such as mania and bipolar disorder may occur in young adults with polymicrogyria (25).

(4) Bilateral parasagittal parieto-occipital polymicrogyria patients present with seizures, cognitive slowing, and normal to mildly decreased intelligence (64).

(5) Bilateral generalized polymicrogyria not limited to the perisylvian region usually have variable degrees of cognitive and motor delay presentation, as well as spastic hemiparesis or quadriparesis and seizures. Most patients also have associated congenital abnormalities such as macrocephaly, scalp and limb defects, low-set ears, macrostomia, hypothyroidism, and sensorineural hearing loss (28; 123). Genetic mutations are the most frequent etiology.

(6) Unilateral polymicrogyria may be seen in various cortical locations, but manifesting signs and symptoms typically include spastic hemiparesis primarily of the upper extremity, variable degrees of mental retardation, and seizures. Contralateral body hemiatrophy and hemianopsia have also been reported in the unilateral forms (26; 129; 132). Unilateral perirolandic polymicrogyria may be accompanied by ipsilateral brainstem hypoplasia and contralateral hyperplasia (127). In unilateral cases, the corticospinal tract, as assessed by MRI and DTI tractography from the involved hemisphere, is asymmetrical and smaller, which may provide for less functional motor impairment if hemispherectomy is performed to control epilepsy because the tract on the other side may carry axons from both hemispheres (54; 06). Even if contralateral hemiparesis is present preoperatively, hemispherectomy may provide good results (97).

Two thirds of patients with polymicrogyria have involvement of the perisylvian region, whether unilateral or bilateral. The characteristic neurologic features reported in patients with perisylvian involvement are cognitive defects, dyspraxia consisting of nasal speech, dysarthria, dysphagia, drooling, and other signs of pseudobulbar palsy (74; 123). The reason for this perisylvian pattern is that about two thirds of the ventral surface of the early telencephalon after prosencephalic cleavage is buried in the frontal and temporal and insular lips of the operculum and, eventually, the Sylvian fissure; ventrodorsal genetic gradients in the vertical axis could be involved in the generation of this abnormal morphogenesis (140).

The spectrum of the conditions associated with polymicrogyria continues expanding. Polymicrogyria has been found part of the heterogeneous genetic presentation of the three forms of the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH1, MPPH2, and MMPH3). MPPH1 is caused by heterozygous mutation in the PIK3R2 gene on chromosome 19p13. MPPH2 is caused by mutation in the AKT3 gene on chromosome 1q43-q44; and MPPH3 is caused by mutation in the CCND2 gene on chromosome 12p13 (61; 01).

Polymicrogyria may occur as an isolated anomaly, but more often, it occurs in conjunction with other developmental abnormalities such as microcephaly, porencephaly, or cerebral encephalocele (38; 166). Fukuyama and colleagues showed thickened cortex with polymicrogyria in all cases of Fukuyama congenital muscular dystrophy with pachygyria/lissencephaly II that were studied neuropathologically (63). Others have classified the neuropathologic abnormalities seen in these patients as Lissencephaly type II (32).

The most frequent and constant association of polymicrogyria is with schizencephaly. Even if schizencephaly is unilateral, the associated polymicrogyria may be bilateral, including a similar topography in the contralateral nonschizencephalic hemisphere. Polymicrogyria occurs within or immediately adjacent to a schizencephalic cleft (63; 11) and involves not only the frontal and temporal lips of the cleft but also the “third lip” of the insula (140). Polymicrogyria may also occur in conjunction with, and in close proximity to focal cortical dysplasia type II (69). Both abnormalities are incited during approximately the same period of cortical organization during fetal development (67; 167). Polymicrogyria not limited to a perisylvian distribution; it rarely may be concurrent with subcortical laminar or “band” heterotopia and can be demonstrated by both prenatal and postnatal MRI (87; 109). Inconstant associations of polymicrogyria may be found in a wide variety of other cerebral malformations, including agenesis of the corpus callosum (70), lissencephalies and holoprosencephaly, and septo-optic-pituitary dysplasia with olfactory bulb hypoplasia (14).

A developmental vasculopathy, hereditary hemorrhagic telangiectasia, can be associated with cerebral aneurysms and ischemic infarcts of the brain; some cases also have bifrontal periventricular nodular heterotopia and perisylvian polymicrogyria (115). A strong coexistence of polymicrogyria is with the megalencephaly-capillary malformation syndrome (previously known as cutis marmorata telangiectasia congenita), associated with PIK3CA mutations of the mTOR signaling pathway (103; 96; 55; 116). Some of these cases can be further complicated by cerebral venous thrombosis (55) or cerebral arteriovenous malformations (86). The vascular disorder is one of angiogenesis during fetal development (86). Another ischemic cause of polymicrogyria during fetal life is twin-to-twin transfusion syndrome (81; 135).

Other associations of polymicrogyria have been demonstrated with neonatal adrenoleukodystrophy (11) and a case of bilateral perisylvian polymicrogyria occurring in a young girl with a Chiari I malformation has been reported. Initially, Robin and colleagues reported 32 patients with deletion of chromosome 22q11.2 and found that there was a striking predilection for right-sided polymicrogyria (131; 23), most common in the perisylvian region and often with mega-cisterna magna or mild cerebellar vermis hypoplasia (120). Nguyen and colleagues reported association of duplication and triplication of chromosome 18q22.2 abnormalities. Focal small foci of polymicrogyria have been identified incidentally within the insular cortex of asymptomatic patients, and focal polymicrogyria has been found associated with chromosome rearrangements detected by CGH microarray analysis (126; 110).

Prognosis and complications

The complications of polymicrogyria are primarily related to epilepsy and cognitive and motor deficits. Neonatal seizures can be severe, refractory to medications, and even life-threatening (20). Prognosis is determined by the underlying etiology as well as distribution and severity of the disease. Poor prognostic indicators include involvement of more than half of one cerebral hemisphere and bilateral brain involvement (08). However, early identification of surgical candidates so they can undergo early epilepsy surgery can improve significantly their developmental outcome (85; 157). In addition to well-known clinical manifestations of epilepsy and cognitive delay, specific disturbances of speech, language, and oral functions may be prominent in perisylvian polymicrogyria (18).

Clinical vignette

A 14-year-old female presented with seizures refractory to medical therapy. At 5 months of age, she was diagnosed with epilepsy consisting of jerking movements, rolling back of her eyes, and a blank stare. Since then, her seizures had occurred at random, but often during the process of awakening from sleep. During the seizures, she also would make a clicking noise with her mouth, and her head would drop forward. The seizures typically occurred two to three times per day and would last 1 to 5 minutes and then subside. Despite various medication regimens, her seizures were poorly controlled. She had moderate mental retardation and developmentally was at the level of a 6- or 7-year-old child. Physical examination revealed slight hypotonia of the upper and lower extremities with decreased deep tendon reflexes and a mildly unsteady gait. MRI with and without gadolinium showed distortion of the frontal right gray-white matter junction with right frontal sulcal and gyral thickening that extended into the right insula.

Polymicrogyria (MRI, axial with contrast)

This axial MRI image with contrast shows thickening of the right frontal cortex with underlying white matter atrophy. (Contributed by Dr. Mohanpal Singh Dulai.)
Polymicrogyria (MR, axial FLAIR)

This axial MRI image shows right frontal cortical thickening with increased FLAIR signal. (Contributed by Dr. Mohanpal Singh Dulai.)

An EEG showed mild generalized slowing, continuous polymorphic slowing in the right frontal region, and frequent epileptiform sharp-wave discharges over the right superior frontal region. Surgical intervention ensued, with resection of the right frontal epileptogenic focus. The resection specimen grossly had a nodular cortical surface with multiple, small coalescent gyri. Microscopically, there was cortical thinning with a simplified lamination pattern and excessive folding of the gyri.

Polymicrogyria (H&E 5x)

A low-power micrograph from a 14-year-old female showing small, fused gyri with abnormal cortical lamination. (Contributed by Dr. Mohanpal Singh Dulai.)
Polymicrogyria (H&E 200x)

A High-power micrograph from a 14-year-old female showing only four layers in the polymicrogyric cortex. (Contributed by Dr. Mohanpal Singh Dulai.)

A diagnosis of polymicrogyria was rendered. After surgery, the patient continued to have refractory seizures; however, the frequency of her seizures was mildly decreased, and the patient was more verbal and interactive than she previously had been.

Biological basis

Etiology and pathogenesis

Until recently, the majority of cases of unilateral and bilateral polymicrogyria were described to be of unknown causes (118; 119). However, advances in the genetic etiologies of brain malformations, including exon sequencing, have revealed multiple specific genes that cause polymicrogyria (47; 153; 03). In addition to the genetic etiologies, environmental etiologies, such as intrauterine infections (eg, cytomegalovirus, toxoplasmosis, syphilis, and varicella-zoster), as well as fetal cerebral ischemia from various causes, such as twin-twin transfusion syndrome, still remain as significant risk factors (38).

Multiple syndromes such as Aicardi syndrome, Foix-Chavany-Marie syndrome, glutaric academia type II, histidinemia, Leigh syndrome, maple syrup urine disease, mitochondrial respiratory chain deficiency, neonatal adrenoleukodystrophy, Pelizaeus-Merzbacher disease, thanatophoric dysplasia, Walker-Warburg and Zellweger syndrome, as well as familial occurrences of polymicrogyria have been confirmed to be due to specific genes that lead to the development of polymicrogyria (73; 99; 146; 168; 24; 112; 124; 35). Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis in many malformations of cortical development including polymicrogyria (93). Hemidystonia with polymicrogyria has been reported with ATP1A3 mutations (91). An association of polymicrogyria with megalencephaly-capillary malformation, which can result in cerebral venous infarctions, has been described (55; 137).

Typically noted at autopsy, the surface of the brain has increased convolutional complexity with miniature gyri that are fused to one another, or piled on top of one another, forming an irregular, bumpy surface.

Polymicrogyria (gross)

This gross image from an autopsy shows small, fused gyri in the perisylvian cortex. (Contributed by Dr. Mohanpal Singh Dulai.)
Polymicrogyria, close-up view

Close-up view of polymicrogyria showing the crowded small gyri. (Contributed by Dr. Hannes Vogel.)
Polymicrogyria affecting both hemispheres

Polymicrogyria affecting both hemispheres and associated with pachygyria; the latter involves the temporal lobes and the medial aspect of the orbital surface of both frontal lobes. (Contributed by Dr. Hannes Vogel.)
Polymicrogyria, cut surface

The heaped-up, concealed, small gyri giving the impression of thick cortex; pachygyria-like. (Contributed by Dr. Hannes Vogel.)

This appearance is often described as that of cobblestones or Moroccan leather (65; 66). The heaping up of the mini-gyri accounts for the apparent cortical thickening that is often seen radiographically (66). The distribution of the lesions often corresponds to a particular arterial territory, most commonly of the middle cerebral artery. Polymicrogyria is often seen at the border of porencephaly or schizencephaly (67).

Polymicrogyria

Polymicrogyria bordering a porencephalic defect. (Contributed by Dr. Hannes Vogel.)

Microscopically, small, fused gyri are noted with shallow sulci. In the unlayered form of polymicrogyria, which is the more common of the two types, there is cortical thinning with the presence of only a molecular layer and a neuronal layer without further laminar organization. In the layered form, four distinct layers of the cortex are seen corresponding to a molecular layer and two layers of neurons separated by an intermediate layer of a few cells and myelinated fibers (65).

Layered polymicrogyria

Schematic representation of the 4-layered cortex. (Used with permission from Churchill Livingston Inc. Crome L, Stern J. The pathology of mental retardation. London: J & A Churchill Ltd., 1967.)
Unlayered and layered polymicrogyria in juxtaposition

Unlayered and 4-layered cortex in juxtaposition. (Used with permission from Elsevier Science Inc. Hevner R, Horoupian D. Pena-Shokeir phenotype associated with bilateral opercular polymicrogyria. Pediatr Neurol 1996;15:348-51.)

Additional histologic findings include an abnormal structure of cortical neurons and presence of heterotopic neurons in the white matter (79).

In acquired forms of the disorder, the more commonly accepted hypothesis is that hypoxic-ischemic insults occur during gestational weeks 20 and 24 (166; 117). Williams and colleagues demonstrated the presence of six layers of the cortex within polymicrogyric regions using Golgi-impregnated tissue. Each layer was continuous with the analogous layer in the adjacent unaffected cortex. However, it was the gyral pattern that was topographically anomalous, inferring that insult had occurred to a normally developed cortex (166). This postmigratory destruction is further supported by the findings that 4-layered polymicrogyria shows normal positioning of neurons in layers II, III, IV, and VI with very few layer V pyramidal cells identified in the sparse intermediate layer. The implication here is that neuronal migration was completed prior to occurrence of the cortical insult (66).

The pattern of distribution of polymicrogyria in the cerebrum and cerebellum tends to correspond to distal regions of perfusion by the major cerebral arteries. Of note, the vasculature of the brain is already established during the first half of gestation, further supporting the post-migrational theory (166). A preference for involvement of the perisylvian may predominantly be due to the fact that this region is more susceptible to intrauterine ischemic insults (159).

In cases resulting from infectious etiologies, neither the degree nor distribution of infection dictates the distribution or extent of polymicrogyria. It is, therefore, likely that the pathogenesis of the disorder relies more heavily on perfusion failure as a result of intrauterine infection rather than direct cytopathic effects of the causative infectious agent (166; 117).

Anatomic observations made by Hallervorden in 1949 and Bankl and Jellinger in 1967 demonstrated cases of classic polymicrogyria in women who had been exposed to large doses of carbon monoxide at 20 and 24 weeks of gestation, respectively (39; 166). This transient perfusion failure occurred in the fetuses at a time when neuronal migration should have been completed.

Animal models. Rat models developed by Dvorak and colleagues showed evidence of a 6-layered cortex in the four layers of polymicrogyric cortex. These findings were similar to those seen by Williams and colleagues just a few years prior. However, the rat models also showed that this phenomenon could occur in the very late stages of neuroblastic migration (46). Dvorak and colleagues also discovered that neuroblasts could migrate through regions of partial necrosis and come to rest in a predetermined layer of the cortex. This meant that intrauterine insult during neuroblastic migration did not necessarily lead to complete migrational arrest (45). Some authors now believe that the intrauterine insult occurs during late neuroblast migration in the unlayered type and post-migration in the layered type of polymicrogyria (63; 117). Focal transcranial cortical freeze lesions in neonatal mice can produce schizencephalic cortex and polymicrogyria, the former yielding increased excitatory synapses with increased dendritic spine density, whereas polymicrogyria produce decreased numbers of inhibitory synapses; both conditions are conducive to epilepsy (44). Induced malformation of neocortex resembling human polymicrogyric cortex in neonatal rats is associated with alterations in dendritic structure and decreased calbindin expression in GABAergic interneurons, but also preservation of glutamate receptors in these cells (83).

Familial cases. Familial cases have been documented with both autosomal dominant and autosomal recessive heredity. Brothers with Joubert syndrome and polymicrogyria have been reported (58). Bilateral frontoparietal polymicrogyria, bilateral perisylvian polymicrogyria, and bilateral generalized polymicrogyria have all shown familial occurrences (90). Bilateral frontal polymicrogyria and bilateral parasagittal parieto-occipital polymicrogyria have only been reported in sporadic cases (73). Bilateral perisylvian polymicrogyria shows a tendency towards occurrence in males. This led to the discovery of a genetic abnormality localized to Xq28. Both unilateral and bilateral perisylvian polymicrogyria have been associated with several chromosomal aneuploidy syndromes. Perhaps the most common genetic abnormality seen with polymicrogyria is deletion of chromosome 22q11.2 (11; 131). It has been reported that deletion of 1p36 is also one of the most common chromosomal abnormalities associated with polymicrogyria (73). An unbalanced translocation resulting in 1q44qter monosomy and 12p13.3pter trisomy has also been identified in some patients with unilateral polymicrogyria (26). Bilateral frontoparietal polymicrogyria has been mapped to 16q12.2-21 and is associated with mutations of the GPR56 gene (11; 73). This gene encodes for a G protein coupled receptor. This regulates cell cycle signaling in neuronal progenitor cells, which is essential in cortical regional patterning (162). Mutations of the PAX6 gene on chromosome 11p13 were seen in a family with unilateral polymicrogyria as well as in mice (73). Xq22 mutations in the SRPX2 gene have been associated with bilateral perisylvian polymicrogyria. This gene is involved the development of the speech cortex through proteolytic remodeling of the extracellular matrix (151; 162). Robin and colleagues have hypothesized that haploinsufficiency of certain genes expressed in vascular tissue that supplies the embryonic brain act in concert with genetic modifying factors, thus, causing hypoperfusion of the developing brain (131). Other mutations reported in polymicrogyria are duplications of 2p16 (04) or of 17p13.3-p13.2 (153). In a Finnish cohort of bilateral perisylvian polymicrogyria, five of 21 (24%) cases were confirmed as de novo with pathological variants of five genes: DDX23, NUS1, SCN3A, TIBA1A, and TUBB2B (76). Genetic mutations were similarly confirmed in one-third of Swedish patients with bilateral polymicrogyria (88).

Other rare genetic mutations that cause familial polymicrogyria and micrencephaly include RTTN (30), COL18A1 (29; 34), NF1A (13), and KIF5C mutations (101). A rare familial autosomal recessive trait is a defect in occludin (OCLN), an important component of the tight junction complex providing apical intercellular connections between adjacent cells in endothelial and epithelial tissues; it is expressed as polymicrogyria and pachygyria, band-like calcifications in basal ganglia and cerebral cortex (probably due to ischemia from endothelial involvement of parenchymal capillaries), and progressive acquired microcephaly; clinical neurologic features are severe global developmental delay and epilepsy (17; 77). Knobloch syndrome is an autosomal recessive disorder consisting of polymicrogyria with early onset of retinal detachment due to vitreoretinal degeneration and occipital cranial defects clinically expressed with refractory severe epilepsy (29; 165). Homozygous mutation of the COL18A1 gene is demonstrated in siblings (29). More details of the diverse genetic profile in polymicrogyria is found below in this review in the Genetics section.

Epileptogenesis in regions of polymicrogyria has received a significant amount of attention in several studies. Some animal studies on polymicrogyric brains have shown hyperexcitability due to a decrease in GABA-A receptors and an increase in postsynaptic glutamate receptors in the microgyric cortex (65). Others have shown that that the hyperexcitability is found in the histologically normal cortex surrounding the polymicrogyria (71; 147). This supports the findings that thalamic sensory afferents are lacking in the microgyric regions and that these afferents are redirected to adjacent areas that become hyperexcitable (65). The gaps in the pial membrane in human polymicrogyria lead to gyral fusion and synaptic short-circuiting of the continuous molecular zones of cortex of adjacent gyri (152; 41); the molecular zone contains almost exclusively glutamaterigc axodendritic synapses, thus, shifting the balance of the excitatory/inhibitory ratio in favor of excitation (138). By contrast, there is dendritic loss in the molecular zone in Down syndrome and epilepsy is uncommon (158). GPR56 promoter of gene expression in GABAergic neurons (and axosomatic synapses) in marmosets also might be altered (107). Corticothalamic circuits also are altered if the thalamus is hypoplastic with polymicrogyria (12).

Neuropathological studies disclose that one of the primary developmental defects in the pathogenesis of polymicrogyria, regardless of etiology, is discontinuity of the pia mater and the glia limitans at the surface of the cortex. Neuropathological series confirm that polymicrogyria is a common end-point of many different etiological processes (75; 160; 48).

Diagnostic workup

Neuroimaging. MRI has been demonstrated to be the most useful and common modality for diagnosing polymicrogyria, as it is more sensitive than any other neuroimaging technique. MRI appearances may vary, revealing multiple small gyri, an apparently thickened cortex with an irregular border between the gray and white matter junction, or even a paradoxically smooth cortex in which a smooth molecular layer fuses over underlying microsulci (67; 09; 155). A reduction in white matter is also common, as are other white matter abnormalities. Patients with deletion of chromosome 22q11.2 may also demonstrate agenesis of the corpus callosum and cerebellar hypoplasia (156). By contrast, some patients have an excessively large corpus callosum with polymicrogyria (21). Large corpus callosum may be a maturational delay or arrest of retraction of commissural collateral axons during fetal and early postnatal life (142). Three-dimensional magnetic resonance imaging is currently the recommended imaging modality as it allows a better appreciation of the true extent of brain involvement. Functional fMRI also is useful in showing decreased reactivity in areas of polymicrogyria (92). Prenatal MRI in the third trimester often can detect polymicrogyria (130).

CT scans have very limited utility in the diagnosis of polymicrogyria. They are helpful to visualize better calcifications due to intrauterine infections and associated band-like calcifications associated with recessive mutations (19; 111).

Diffusion tensor imaging (DTI) and functional MRI in unilateral polymicrogyria in nine patients demonstrated asymmetry in the corticospinal tract at the level of the midbrain cerebral peduncles; pronounced asymmetry predicted preserved motor function after hemispherectomy because of bilateral projections of the CST from the preserved hemisphere that arose during fetal life (54).

Neurophysiology. Electroencephalography, including routine and prolonged video-EEG monitoring, is used to characterize the background and the interictal and ictal patterns that define the features of each of the structural epileptic syndromes due to the various forms of malformations of cortical development seen in this condition. In a study, 10 of 16 patients with polymicrogyria had normal EEG activity. The remaining six had at least focal abnormalities, and three of those also had generalized EEG abnormalities (159). Teixeira and colleagues also showed that EEG abnormalities were most often seen in patients with generalized, hemispheric, and holosylvian polymicrogyria. There was a good correlation between extent of cortical involvement and severity of clinical features and EEG abnormalities. There is a positive correlation between a slow background on EEG and the presence of cognitive delay, motor deficit, and epilepsy. However, a majority of the patients they studied (55%) had no EEG abnormalities whatsoever (159). In patients with perisylvian polymicrogyria, epileptiform activity, when present, is typically localized to the frontotemporal and temporal regions, and non-epileptiform abnormalities are more often seen in the cortico-temporal regions (159). It should be taken in consideration that many children could present initially with generalized onset ictal patterns, such as diffuse electrodecremental response or generalized paroxysmal fast activity, but subsequently, these children can be identified later to have focal epileptogenic zones that could make them amenable to potentially successful epilepsy surgery, with the help of techniques such as SISCOM guided depth electrodes implantation prior to resection of an epileptogenic zone. Continuous spike-wave complexes during sleep in polymicrogyria are likely related to cortico-thalamic circuitry (12). Electroclinical changes from infancy to adulthood after corpus callosotomy were described in three siblings with bilateral frontoparietal polymicrogyria (90). fMRI studies suggest that polymicrogyric cortex may predispose to seizures via abnormal network topology (144; 69; 33). Combined EEG and invasive epileptogenicity mapping in pediatric patients with refractory epilepsy and focal polymicrogyria may be useful to surgical decisions of brain resection (143).

Neuropathology. Excellent gross and microscopic neuropathological studies of polymicrogyria are available (152; 41). Gross inspection at autopsy or by neuroimaging, especially MRI, disclose polymicrogyria as focal clusters of excessively small and too numerous gyri within a given region of neocortex; the distribution is perisylvian, focal in other regions, or generalized throughout the cortex.

Generalized polymicrogyria

Gross lateral view of cerebral hemisphere of a term neonate with generalized bilateral polymicrogyria. The normal pattern of gyration is not observed in any lobe. Gyri are small and excessive in number, and many of the sulci separ...

But microscopic examination reveals a great deal more, particularly if histological stains are supplemented by immunocytochemical reactivities. The laminar structure of the microgyria may be preserved, but the number of neurons reduced (78), or there may be dyslamination with unlayered architecture or disorganized and disoriented neurons (51; 52). Radial micro-columnar architecture, such as that which occurs in focal cortical dysplasia type I and in normal cortical histogenesis during the first half of gestation, is found occasionally, especially in perisylvian polymicrogyria associated with schizencephaly (16).

One of the most striking and important neuropathological features that is not appreciated in neuroimaging is the gaps or discontinuities in the pia mater that enables fusion of adjacent microgyria with continuity of their molecular zones (78; 152; 75; 41). Synaptophysin immunoreactivity shows synaptic activity across this abnormal continuity of the molecular zone between gyri at abnormal sites (16). Short-circuitry of mainly excitatory synapses of the fused molecular zones of adjacent microgyria is an explanation of why polymicrogyria often is epileptogenic (138). Recurrent interactions in local circuits are a neurophysiological basis of seizure generation (122).

Synaptophysin immunoreactivity

Patient is a 7-month-old infant with focal refractory epilepsy since the neonatal period emanating from region of perisylvian polymicrogyria; surgical resection abolished most seizures and rendered residual postoperative epilepsy ...

This pattern of fused gyri is seen in polymicrogyria of all etiologies, and there is no correlation with lamination patterns of the cortex of the gyri (75). However, gyral fusion is more extensive and more frequent in genetic forms of polymicrogyria than in acquired forms such as ischemic encephalopathy (Sarnat unpublished data). This may explain why some cases are much less epileptogenic than others. Gaps in the pia limitans enable overmigration of neuroblasts and glial cells into the leptomeninges within the shallow sulci above the areas of fusion of the molecular zones of adjacent gyri (152). Physical properties of the leptomeninges are also altered by thickening and reduplication of the pial collagen layer and increased meningeal vascularity.

In addition, there is clustering of Cajal-Retzius neurons in the molecular zones of microgyria with persistent Reelin production, which contributes to the dyslamination of the cortex and also may favor epilepsy (49; 100; 75; 41). Another factor to explain epilepsy in polymicrogyria is that the expression of keratan sulfate, a normal extracellular proteoglycan that binds to neuronal membranes during development, but not to dendritic spines, and selectively repels the formation of glutamatergic (excitatory) synapses while enabling GABAergic (inhibitory) synapses is deficient in cortical zones of polymicrogyria (139). Excessive heterotopic neurons and synaptic plexi in the U-fibre layer beneath polymicrogyria also may contribute to the epileptogenic malformation (141).

In fetuses of 18 to 29 weeks gestational age who had suffered ischemic infarcts of the cortex with focal necrosis, adjacent cortex often had polymicrogyria with pial defects and also an inflammatory response of astroglia and microglia (41). Cajal-Retzius neurons of layer one (molecular zone) were hyperplastic, clustered, and sometimes displaced deep within the cortical plate; subplate neurons also were hypertrophic, particularly in young fetuses of less than 20 weeks gestation. Radial glial fibers by 18 weeks showed altered growth patterns with abnormal lateral branching (41). In a 5-year-old boy with refractory focal epilepsy, a rare neuroanatomical pattern of unilateral cortical neuronal loss in layer four and peripheral polymicrogyria was demonstrated (95).

Genetics. Nearly all cases of polymicrogyria confirmed by neuroimaging merit genetic investigation unless another cause, such as a congenital infection, is demonstrated. Multiple specific genes can cause polymicrogyria (43; 47; 153; 48; 03). The most frequent mutations in a deep sequencing study of 123 patients were TUB1A and PIK3R2, but others included PIK2CA, NEDD4L, COL4A1, GPPSM2, GRIN2B, WDR62, TUBB2B, TUBB3, ACTG1, and FH (153). Some, such as the PIK family of genes, are part of the mTOR signaling pathway that causes megalocytic dysmorphic neurons. Other candidate genes, such as de novo missense variants, are PANX1, QRICH1, SCN2A, and compound heterozygous variants in TMEM161A, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families (03). Other isolated case reports associate polymicrogyria with ATP1A3 (91), ADGRG1 (90), SCN2A (57), and the channelopathy gene KCNMA1 (60).

Novel human polymicrogyria loci are demonstrated at 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2 (43). Genetic techniques such as comparative genome hybridization and whole-exome sequencing are important in diagnosis (15; 80). Deletion of chromosome 22q11.2 in patients with polymicrogyria, especially perisylvian polymicrogyri, was reported by Robin and colleagues to be the most common genetic abnormality associated with polymicrogyria (131). Testing for the GPR56 gene should be pursued in all patients with bilateral frontoparietal polymicrogyria (11). Copy number variants (CNVs) also play an important role in the etiology spectrum of the malformations seen in polymicrogyria, either as direct cause or as genetic risk factors. Mutations of the phosphoinositide-3-kinase regulatory subunit PIK3R2 can result in perisylvian polymicrogyria (102). The SCN3A gene encodes sodium channel Nav1.3 that is highly expressed in the brain, and missense variants of this gene cause severe infantile epileptic encephalopathy and impaired oral motor development, profound intellectual disability and diffuse generalized polymicrogyria (169; 149). The closely related SCN2A gene can produce Ohtahara syndrome with seizure onset within a day after birth, perisylvian polymicrogyria, and white matter heterotopia (163).

The genetic involvement leading to polymicrogyria can be divided in two types: one due to ischemia-related genes and another due structural function-related genes. Mutations that lead to ischemia where polymicrogyria has been found include alterations of the Occludin gene (OCLN), the COL4A1/COL4A2 gene, the ALX4 and MSX2 gene, deletions in the 22Q11, and the somatic mutation in GNAQ that causes the Sturge-Weber syndrome. CCND2 mutation results not only in perisylvian polymicrogyria but also obstructive hydrocephalus and somatic anomalies, including postaxial polydactyly (98). Brain malformations in CCND2 not only involve the cortex, but also may include dysplasia and hypoplasia of brainstem structures and cerebellum, and hypomyelination (22). Multisystemic developmental anomalies also occur in Pallister-Killian syndrome caused by mosaic tetrasomy of chromosome 12p; the brain malformations are bilateral perisylvian polymicrogyria, ventriculomegaly, and hypoplasia of the corpus callosum (125). GRIN1 is another now established genetic association with polymicrogyria (37).

Genetic mutations that primarily cause disruption of the neuronal structural organization include multiple new genes that encode proteins that participate in the integrity of the centrosome, cilia, and microtubule, as well as proteins that participate in the integrity of the basement membrane. The more important genes are the GPR56 and the tubulin genes, which are mutated in many malformations of cerebral cortical development including in polymicrogyria (133).

In generalized bihemispheric polymicrogyria, a strong association is seen in the tubulinopathies (50; 134). Polymicrogyria has been reported in patients with mutations in TUBA1A, TUBB2B, TUBB3, and TUBA8. Mutations of the TUBB2B are known to cause asymmetric polymicrogyria (72; 153). The association of TUBA1A mutation was reported to cause eye abnormalities polymicrogyria, agenesis of the corpus callosum, microcephaly, and refractory epilepsy (108). Extensive bilateral polymicrogyria also is seen with de novo mutations in the gene GRIN1, which encodes GluN1, the essential subunit of the N-methyl-D-aspartate (NMDA) receptor (56). Mutation of the LAMC3 gene also causes generalized polymicrogyria (170).

Mutations of the PIK3CA and other PI3K-AKT-mTOR pathway genes have been identified in several overgrowth syndromes associated with polymicrogyria, such as hemimegalencephaly (40; 104; 153; 154). Pathogenic variants in PTEN also can be associated with polymicrogyria (145).

Other genes found to be associated with polymicrogyria include mutations of the WDR62 (WD Repeat Domain 62) gene, as well as mutations of the EOMES (Eomesodermin) gene, which encodes a transcription factor that influences regional gene expression and is involved in implementing regional identity in the cortex. Finally, mutations of the LAMC3 (laminin, gamma 3) gene are associated with occipital polymicrogyria. ATP1A3 variants were found in 124 patients with polymicrogyria by whole-exome sequencing (105).

The autosomal dominantly inherited BICD2 gene is associated with a form of congenital-onset spinal muscular atrophy and arthrogryposis multiplex congenita, but the phenotype is now expanded to also include microcephaly, bilateral perisylvian polymicrogyria, micrognathia, and respiratory insufficiency in the neonatal period (128).

Pallister-Killian syndrome, a rare disorder caused by mosaic tetrasomy of chromosome 12p and characterized by facial dysmorphism, hypotonia, developmental delay, and epilepsy, also exhibits polymicrogyria and may include cerebral calcifications (68).

Given the diversity of genes found to be involved in the etiology of this condition, the availability of next-generation sequencing could make the detection of multiple genes that cause polymicrogyria more cost effective (47).

Laboratory. There is no specific biochemical testing for the diagnosis of polymicrogyria; however, very long chain fatty acids should be obtained if there is a strong suspicion of Zellweger syndrome (66).

Media

References

01: Adam MP, Mirzaa GM, Pagon RA, et al. MPPH syndrome. GeneReviews (Internet) 2022.
02: Agarwal A, Goyal M, Jain J, Agarwal A. Congenital perisylvian syndrome presenting as post-partum seizures with preeclampsia. J Assoc Physicians India 2017;65(6):103-5. PMID 28782324
03: Akula SK, Chen AY, Neil JE, et al. Exome sequencing and identification of new genes and shared mechanisms in polymicrogyria. JAMA Neurol 2023;80(9):980-8. PMID 37486637
04: Amrom D, Poduri A, Goldman JS, et al. Duplication 2p16 is associated with perisylvian polymicrogyria. Am J Med Genet A 2019;179(12):2343-56. PMID 31660690
05: Andelman-Gur MM, Leventer RJ, Hujirat M, et al. Bilateral polymicrogyria associated with dystonia: a new neurogenetic syndrome? Am J Med Genet A 2020;182(10):2207-13. PMID 33001581
06: Arrigoni F, Peruzzo D, Mandelstam S, et al. Characterizing white matter tract organization in polymicrogyria and lissencephaly: a multifiber diffusion MRI modeling and tractography study. Am J Neuroradiol 2020;41(8):1495-502. PMID 32732266
07: Baba S, Okanishi T, Nishimura M, et al. Effectiveness of total corpus callosotomy for diffuse bilateral polymicrogyria: report of three pediatric cases. Brain Dev 2018;40(8):719-23. PMID 29622280
08: Barkovich AJ. Current concepts of polymicrogyria. Neuroradiology 2010a;52(6):479-87. PMID 20198472
09: Barkovich AJ. MRI analysis of sulcation morphology in polymicrogyria. Epilepsia 2010b;51(Suppl 1):17-22. PMID 20331706
10: Barkovich J. Complication begets clarification in classification. Brain 2013;136(Pt 2):368-73. PMID 23413256
11: Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. A developmental and genetic classification for malformations of cortical development. Neurology 2005;65(12):1873-87. PMID 16192428
12: Bartolini E, Falchi M, Zellini F, et al. The syndrome of polymicrogyria, thalamic hypoplasia, and epilepsy with CSWS. Neurology 2016;86(13):1250-9. PMID 26944271
13: Bayat A, Kirchhoff M, Madsen CG, Roos L, Kreiborg S. Familial craniofacial abnormality and polymicrogyria associated with a microdeletion affecting the NFFIA gene. Clin Dysmorphol 2017;26(3):148-53. PMID 28452798
14: Benson JC, Nascene D, Truwit C, McKinney AM. Septo-optic dysplasia: assessment of associated findings with special attention to the olfactory sulci and tracts. Clin Neuroradiol 2019;29(3):505-13. PMID 29663010
15: Bilguvar K, Oztürk AK, Louvi A, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 2010;467(7312):207-10. PMID 20729831
16: Blumcke I, Sarnat HB, Coras R. Surgical Neuropathology of Focal Epilepsies: Textbook and Atlas. Montrouge, France: John Libbey Eurotext, 2015:44-6.
17: Borges-Medeiros R, Mendes de Oliveira JR. A commentary on band-like calcifications with simplified gyration and polymicrogyria: report of 10 new families and identification of five novel OCLN mutations. J Hum Genet 2018;63(2):255-6. PMID 29192239
18: Branden RO, Leventer RJ, Jansen A, Scheffler IE, Morgan AT. Speech and language in bilateral perisylvian polymicrogyria: a systematic review. Dev Med Child Neurol 2019;61(10):1145-52. PMID 30680716
19: Briggs TA, Wolf NI, D'Arrigo S, et al. Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype. Am J Med Genet A 2008;146a(24):3173-80. PMID 19012351
20: Brna PM, Harvey AS, Leventer RJ. Hemispheric polymicrogyria and neonatal seizures: a potentially life-threatening combination. Epileptic Disord 2017;19(1):87-93. PMID 28300030
21: Budai C, Moscato G, Patruno F, Leonardi M, Maffei M. Polymicrogyria, large corpus callosum and psychomotor retardation in four-year-old girl: potential association based on MR findings. A case report and literature review. Neuroradiol J 2014;27(5):590-4. PMID 25260206
22: Cappuccio G, Ugga L, Parrini E, D’Amico A, Brunetti-Pierri N. Severe presentation and complex brain malformations in an individual carrying a CCND2 variant. Mol Genet Genomic Med 2019;7(6):e708. PMID 31056854
23: Castro A, Rodrigues N, Pereira M, Goncalves C. Bilateral polymicrogyria: always think in chromosome 22q11.2 deletion syndromes. BMJ Case Rep 2011;2011. PMID 22674744
24: Cellini E, Disciglio V, Novara F, et al. Periventricular heterotopia with white matter abnormalities associated with 6p25 deletion. Am J Med Genet A 2012;158A(7):1793-7. PMID 22678982
25: Chacón-González J, Resstrepo-Martínez M, Moreno-Avellan A, Ramirez-Bermudez J. Polymicrogyria: an unusual case of secondary mania. J Psychiatri Pract 2023;29(5):415-20. PMID 37678371
26: Chang BS, Apse KA, Caraballo R, et al. A familial syndrome of unilateral polymicrogyria affecting the right hemisphere. Neurology 2006;66(1):133-5. PMID 16401865
27: Chang BS, Piao X, Bodell A, et al. Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003;53(5):596-606. PMID 12730993
28: Chang BS, Piao X, Giannini C, et al. Bilateral generalized polymicrogyria (BGP): a distinct syndrome of cortical malformation. Neurology 2004;62(10):1722-8. PMID 15159468
29: Charsar BA, Goldberg EM. Polymicrogyria and intractable epilepsy in siblings with Knobloch syndrome and homozygous mutation of COL18A1. Pediatr Neurol 2017;76:91-2. PMID 28950998
30: Chartier S, Alby C, Boutaud L, et al. A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern. Birth Defects Res 2018;110(7):598-602. PMID 29356416
31: Cho WH, Seidenwurm D, Barkovich AJ. Adult-onset neurologic dysfunction associated with cortical malformations. AJNR Am J Neuroradiol 1999;20(6):1037-43. PMID 10445440
32: Clement E, Mercuri E, Godfrey C, et al. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann Neurol 2008;64(5):573-82. PMID 19067344
33: Cohen N, Ebrahimi Y, Medvedovsky M, et al. Interictal epileptiform discharge dynamics in perisylvian polymicrogyria using EEG-fMRI. Front Neurol 2021;12:658239. PMID 34149595
34: Corbett MA, Turner SJ, Gardner A, et al. Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations. Eur J Med Genet 2017;60(8):437-43. PMID 28602933
35: Cordelli DM, Garavelli L, Savasta S, et al. Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype. Am J Med Genet A 2013;161A(2):273-84. PMID 23322667
36: Courtier J, Schauer GM, Parer JT, Regenstein AC, Callen PW, Glenn OA. Polymicrogyria in a fetus with human parvovirus B19 infection: a case with radiologic-pathologic correlation. Ultrasound Obstet Gynecol 2012;40(5):604-6. PMID 22344957
37: Crino P. Polymicrogyria and GRIN1 mutations: altered connections, altered excitability. Brain 2018;141(3):622-8. PMID 30753417
38: Crome L. Microgyria. J Pathol Bacteriol 1952;64(3):479-95. PMID 12981610
39: Crome L, France NE. Microgyria and cytomegalic inclusion disease in infancy. J Clin Pathol 1959;12:427-34. PMID 13812952
40: Cushion TD, Dobyns WB, Mullins JG, et al. Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. Brain 2013;136(Pt 2):536-48. PMID 23361065
41: Diamandis P, Chitayat D, Toi A, Blaser S, Shannon P. The pathology of incipient polymicrogyria. Brain Dev 2017;39(1):23-39.** PMID 27406708
42: Dies KA, Bodell A, Hisama FM, et al. Schizencephaly: association with young maternal age, alcohol use, and lack of prenatal care. J Child Neurol 2013;28(2):198-203. PMID 23266945
43: Dobyns WB, Mirzaa G, Christian SL, et al. Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36,3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2. Am J Med Genet Part A 2008;146A(13):1637-54. PMID 18536050
44: Dos Santos Heringer L, Rios Carvalho J, Teixeira Oliveira J, et al. Altered excitatory and inhibitory neocortical circuitry leads to increased convulsive severity after pentylnetetrazol injection in an animal model of schizencephaly, but not of microgyria. Epilepsia Open 2022;7(3):462-73. PMID 35808864
45: Dvorak K, Feit J. Migration of neuroblasts through partial necrosis of the cerebral cortex in newborn rats-contribution to the problems of morphological development and developmental period of cerebral microgyria. Histological and autoradiographical study. Acta Neuropathol (Berl) 1977;38(3):203-12. PMID 899721
46: Dvorak K, Feit J, Jurankova Z. Experimentally induced focal microgyria and status verrucosus deformis in rats--pathogenesis and interrelation. Histological and autoradiographical study. Acta Neuropathol (Berl) 1978;44(2):121-9. PMID 716839
47: Dyment DA, Sawyer SL, Chardon JW, Boycott KM. Recent advances in the genetic etiology of brain malformations. Curr Neurol Neurosci Rep 2013;13(8):364. PMID 23793931
48: Epilepsy Phenome/Genome Project Epi4K Consortium. Diverse genetic causes of polymicrogyria with epilepsy. Epilepsia 2021;62(4):973-83. PMID 33818783
49: Eriksson SH, Thom M, Heffernan J, et al. Persistent reelin-expressing Cajal-Retzius cells in polymicrogyria. Brain 2001;124(Pt 7):1350-61. PMID 11408330
50: Fallet-Bianco C, Laquerrière A, Poirier K, et al. Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlisssencephaly. Acta Neuropathol Commun 2014;2:69. PMID 25059107
51: Ferrer I. A Golgi analysis of unlayered polymicrogyria. Acta Neuropathol 1984;65:69-76. PMID 6516803
52: Ferrer I, Catala I. Unlayered polymicrogyria: structural and developmental aspects. Anat Embryol 1991;184(5):517-28. PMID 1741482
53: Feucht F, Vaast P, Bonniere M, et al. Amniotic bands and associated polymicrogyria: in favor of a unique ischemic cause. Eur J Obstet Gynecol Reprod Biol 2019;236:252-54. PMID 30955893
54: Foesleitner O, Nenning KH, Traub-Weidinger T, et al. Assessing corticospinal tract asymmetry in unilateral polymicrogyria. Am J Neuroradiol 2018;39(8):1530-5. PMID 29954815
55: Fortin O, Ashour M, Lacroix C, et al. Megalencephaly-capillary malformation-polymicrogyria with cerebral venous thrombosis. Can J Neurol Sci 2020;47(6):828-9. PMID 32631464
56: Fry AE, Fawcett KA, Zelnik N, et al. De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain 2018;141(3):698-712. PMID 29365063
57: Gelot AB, Courtin T, Sileo C, et al. Polymicrogyria with dysmorphic neurons in a patient with SNCA2 mutation. J Neuropathol Exp Neurol 2022;81(9):758-61. PMID 35788683
58: Giordano L, Vignoli A, Pinelli L, et al. Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers. Am J Med Genet 2009;149A(7):1511-5. PMID 19533793
59: Glenn OA, Cuneo AA, Barkovich AJ, Hashemi Z, Bartha AI, Xu D. Malformations of cortical development: diagnostic accuracy of fetal MR imaging. Radiology 2012;263(3):843-55. PMID 22495681
60: Graber D, Imagawa E, Miyake N, et al. Polymicrogyria in a child with KCNMA1-related channelopathy. Brain Dev 2022;44(2):173-7. PMID 34674900
61: Gripp KW, Hopkins E, Vinkler C, et al. Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly polymicrogyria-polydactyly hydrocephalus syndromes. Am J Med Genet 2009;149A(5):868-76. PMID 19353582
62: Guerrini R, Barkovich AJ, Sztriha L, Dobyns WB. Bilateral frontal polymicrogyria: a newly recognized brain malformation syndrome. Neurology 2000;54(4):909-13. PMID 10690985
63: Guerrini R, Carrozzo R. Epilepsy and genetic malformations of the cerebral cortex. Am J Med Genet 2001;106(2):160-73. PMID 11579436
64: Guerrini R, Dubeau F, Dulac O, et al. Bilateral parasagittal parietooccipital polymicrogyria and epilepsy. Ann Neurol 1997;41(1):65-73. PMID 9005867
65: Harding B, Copp AJ. Malformations. In: Graham DI, Lantos, PL, editors. Greenfield's Neuropathology. 7th Ed. Vol 1. London: Arnold, 2002:406-9.
66: Harding BN, Pilz DT. Polymicrogyria. In: Golden JA, Harding BN, editors. Developmental Neuropathology. Switzerland: The International Society of Neuropathology, 2004:49-51.
67: Hayashi N, Tsutsumi Y, Barkovich AJ. Polymicrogyria without porencephaly/schizencephaly. MRI analysis of the spectrum and the prevalence of macroscopic findings in the clinical population. Neuroradiology 2002;44(8):647-55. PMID 12185542
68: Hiraiwa A, Matsui K, Nakayama Y, et al. Polymicrogyria with calcification in Pallister-Killian syndrome detected by microarray analysis. Brain Dev 2021;43(3):448-53. PMID 33229101
69: Hong SJ, Bernhardt BC, Gill RS, Bernasconi N, Bernasconi A. The spectrum of structural and functional network alaaterations in malformations of cortical development. Brain 2017;140(8):2133-43. PMID 28899007
70: Im K, Grant PE. Sulcal pits and patterns in developing human brains. Neuroimage 2018. PMID 29601953
71: Isik U, Dincer A, Ozek MM. Surgical treatment of polymicrogyria with advanced radiologic and neurophysiologic techniques. Childs Nerv Syst 2007;23(4):443-8. PMID 17171381
72: Jaglin XH, Poirier K, Saillour Y, et al. Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet 2009;41(6):746-52. PMID 19465910
73: Jansen A, Andermann E. Genetics of the polymicrogyria syndromes. J Med Genet 2005;42(5):369-78. PMID 15863665
74: Jansen AC, Leonard G, Bastos AC, et al. Cognitive functioning in bilateral perisylvian polymicrogyria (BPP): clinical and radiological correlations. Epilepsy Behav 2005;6(3):393-404. PMID 15820349
75: Jansen AC, Robitaille Y, Honavar M, et al. The histopathology of polymicrogyria: a series of 71 brain autopsy studies. Dev Med Child Neurol 2016;58(1):39-48.** PMID 26179148
76: Jarvela I, Paetau R, Rajjendran Y, et al. Heterogeneous genetic patterns in bilateral perisylvian polymicrogyria: insights from a Finnish family cohort. Brain Commun 2024;6(3):fcae142. PMID 38712318
77: Jenkinson EM, Livingston JH, O’Driscoll MC, et al. Comprehensive molecular screening strategy of OCLN in band-like calcification with simplified gyration and polymicrogyria. Clin Genet 2018;93(2):228-34. PMID 28386946
78: Judkins AR, Martínez D, Ferreira P, Dobyns WB, Golden JA. Polymicrogyria includes fusion of the molecular layer and decreased neuronal populations but normal lamnar organization. J Neuropathol Exp Neurol 2011;70(6):438-43. PMID 21572338
79: Kakita A. Surgical pathologic features of cerebral cortical lesions taken from 600 patients with intractable epilepsy. Brain Dev 2013;35(8):793-801. PMID 23628381
80: Kariminejad R, Lind-Thomsen A, Tümer Z, et al. High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations. Hum Mutat 2011;32(12):1427-35. PMID 21882292
81: Karner E, Kasprian GJ, Farr A, et al. Polymicrogyria in a patient after twin-twin transfusion syndrome. BMJ Case Rep 2023;16(9):e255510. PMID 37739446
82: Kelani AB, Sanoussi S, Mamadou MG, Catala M. Polymicrogyria, aventriculy, polydactyly, encephalocele, callosal agenesis (PAPEC): a new syndrome? Childs Nerv Syst 2022;38(10):2029-32. PMID 35476093
83: Kharazia VN, Jacobs KM, Prince DA. Light microscopic study of GluR1 and calbindin expression in interneurons of neocortical microgyral malformations. Neuroscience 2003;120(1):207-18. PMID 12849753
84: Kim HI, Lee MC, Lee JS, et al. Bilateral perisylvian ulegyria: clinicopathological study of patients presenting with pseudobulbar palsy and epilepsy. Neuropathology 2006;26(3):236-42. PMID 16771181
85: Kimura N, Takahashi Y, Shigematsu H, et al. Pediatric epilepsy surgery, advantage of early recognition of candidates - from developmental outcome. No To Hattatsu 2013;45(3):199-205. PMID 23785834
86: Klostranec JM, Chen L, Mathur S, et al. A theory for polymicrogyria and brain arteriovenous malformations in HHT. Neurology 2019;92(1):34-42. PMID 30584075
87: Kobayashi Y, Hojo M, Magara S, et al. Epilepsy characteristics and clinical outcomes in a patient with megalencephaly, polymicrogyria and ribbon-like band heterotopia. [Abstract]. Brain Dev 2017;39:148.
88: Kolbjer A, Martin Muñoz DA, Örtqvist AK, et al. Polymicrogyria: epidemiology, imaging, and clinical aspecs in a population-based cohort. Brain Commun 2023;5(4):fcad213. PMID 37614989
89: Kuchukhidze G, Unterberger I, Dobesberger J, et al. Electroclinical and imaging findings in ulegyria and epilepsy: a study on 25 patients. J Neurol Neurosurg Psychiatry 2008;79(5):547-52. PMID 17682014
90: Kuo CY, Tsai MH, Lin HH, et al. Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral frontoparietal polymicrogyria: the electroclinical change from infancy to adulthood after callosotomy in three siblings. Epilepsia Open 2023;8(1):154-64. PMID 26524291
91: Lacombe D, Van-Gils J, Lebrun M, et al. Hemidystonia with polymicrogyria in part of ATP1A3-related disorders. Brain Dev 2022;44(8):567-70. PMID 35623960
92: Lenge M, Barba C, Montanaro D, Aghakhanyan G, Frijia F, Guerrini R. Relationships between morphologic and functional patterns in the polymicrogyric cortex. Cereb Cortex 2018;28(3):1076-86. PMID 28334078
93: Lennox AL, Hoye ML, Jiang R, et al. Pathogenic DDX3X mutations impair RNA metabolism and neurogeneisis during fetal cortical development. Neuron 2020;106(3):404-20. PMID 32135084
94: Leventer RJ, Jansen A, Pilz DT, et al. Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. Brain 2010;133(Pt 5):1415-27. PMID 20403963
95: Lin J, Yu JB, Liu Y, et al. Rare pathological combination of unilateral cortex neuronal loss of layer four and polymicrogyria – a case report. Seizure Eur J Epilepsy 2022. In press.
96: Loughan AAR, Harrell M, Pema R, Allen A, Suddarth B. Megalencephaly-capillary malformation polymicrogyria: a review and complex pediatric case report. Appl Neuropsychol Child 2017;6(4):369-72. PMID 27216985
97: Maillard L, Ramantanni G. Epilepsy surgery for polymicrogyria: a challenge to be undertaken. Epileptic Disord 2018;20(5):319-38. PMID 30378553
98: Maini I, Farnetti E, Caraffi SG, et al. A novel CCND2 mutation in a previously reported case of megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus. Neuropediatrics 2018;49(3):222-4. PMID 29642246
99: Mellado C, Poduri A, Gleason D, et al. Candidate gene sequencing of LHX2, HESX1, and SOX2 in a large schizencephaly cohort. Am J Med Genet A 2010;152A(11):2736-42. PMID 20949537
100: Meyer G. Building a human cortex: the evolutionary differentiation of Cajal-Retzius cells and the cortical hem. J Anat 2010;217(4):334-43. PMID 20626498
101: Michels S, Foss K, Park K, et al. Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical development. Am J Med Genet A 2017;173(12):3127-31. PMID 29048727
102: Mirzaa GM, Conti V, Timms AE, et al. Characterization of mutations of the phophoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study. Lancet Neurol 2015;14(12):1182-95. PMID 26520804
103: Mirzaa GM, Conway RL, Gripp KW, et al. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A 2012;158A(2):269-91. PMID 22228622
104: Mirzaa GM, Rivière JB, Dobyns WB. Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. Am J Med Genet C Semin Med Genet 2013;163(2):122-30. PMID 23592320
105: Miyatake S, Kato M, Kumamoto T, et al. De novo ATP1A3 variants cause polymicrogyria. Sci Adv 2021;7(13):eabd2368. PMID 33762331
106: Montenegro MA, Cendes F, Lopes-Cendes I, Guerreiro CA, Li LM, Guerreiro MM. The clinical spectrum of malformations of cortical development. Arq Neuropsiquiatr 2007;65(2A):196-201. PMID 17607413
107: Murayama A, Kuwako K-I, Okahara J, et al. The polymicrogyria-associated GPR56 promoter preferentially drives gene expression in developing GABAergic neurons in common marmosets. Sci Rep 2020;10(1):21516. PMID 33299078
108: Myers KA, Bello-Espinosa LE, Kherani A, Wei XC, Innes AM. TUBA1A mutation associated with eye abnormalities in addition to brain malformation. Pediatr Neurol 2015;53(5):442-4. PMID 26294046
109: Nagaraj UD, Hopkin R, Schapiro M, Kline-Fath B. Prenatal and postnatal evaluation of polymicrogyria with band heterotopia. Radiol Case Rep 2017;12(3):602-5. PMID 28828134
110: Nguyen-Minh S, Drossel K, Horn D, Rost I, Spors B, Kaindl AM. Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly, mental retardation and leukencephalopathy. Gene 2013;523(1):92-8. PMID 23566840
111: O'Driscoll MC, Daly SB, Urquhart JE, et al. Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am J Hum Genet 2010;87(3):354-64. PMID 20727516
112: Oegema R, Maat-Kievit A, Lequin MH, et al. Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. Am J Med Genet A 2012;158a(6):1472-6. PMID 22585566
113: Oliveira EP, Hage SR, Guimaraes CA, et al. Characterization of language and reading skills in familial polymicrogyria. Brain Dev 2008;30(4):254-60. PMID 17920799
114: Ortiz JF, Ruxmohan S, Khurana M, Hidalgo J, Alzamora IM, Patel A. Megalencephaly polymicrogyria polydactyly hydrocephalus (MPPH): a case report and review of the literature. Cureus 2021;13(7):e16132. PMID 34354878
115: Palagallo GJ, McWilliams SR, Sekarski LA, Sharma A, Goyal MS, White AJ. The prevalence of malformations of cortical development in a pediatric hereditary hemorrhagic telangiectasia population. AJNR Am J Neuroradiol 2017;38(2):383-6. PMID 28059706
116: Park HJ, Shin CH, Yoo WJ, et al. Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations. Orphanet J Rare Dis 2020;15(1):205. PMID 32778138
117: Pascual-Castroviejo I, Pascual-Pascual SI, Viano J, Martinez V, Palencia R. Unilateral polymicrogyria: a common cause of hemiplegia of prenatal origin. Brain Dev 2001;23(4):216-22. PMID 11376999
118: Pascual Castroviejo I, Pascual Pascual SI, Viano J, Martinez V, Palencia R. Malformations of cortical development and their clinical repercussions in a series of 144 cases. Rev Neurol 2003;37(4):327-44. PMID 14533110
119: Pascual Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Viaño Lopez J. Congenital cytomegalovirus infection and cortical/subcortical malformations. Neurologia 2012;27(6):336-42. PMID 22365270
120: Patel S, Barkovich AJ. Analysis and classification of cerebellar malformations. AJNR Am J Neuroradiol 2002;23(7):1074-87. PMID 12169461
121: Pearl PL, Poduri A, Prabhu SP, et al. White matter spongiosis with vigabatrin therapy for infantile spasms. Epilepsia 2018;59(4):e40-4. PMID 29473152
122: Peron S, Pancholi R, Voelcker B, et al. Recurrent interactions in local cortical circuits. Nature 2020;579(7798):256-9. PMID 32132709
123: Poduri A, Chitsazzadeh V, D’Arrigo S, et al. The syndrome of perisylvian polymicrogyria with congenital arthrogryposis. Brain Dev 2010;32(7):550-5. PMID 19751967
124: Poduri A, Evrony GD, Cai X, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 2012;74(1):41-8. PMID 22500628
125: Poulton C, Baynam G, Yates C, et al. A review of structural brain abnormalities in Pallister-Killian syndrome. Mol Genet Genomic Med 2018;6(1):92-8. PMID 29222831
126: Quelin C, Saillour Y, Poirier K, et al. Focal polymicrogyria are associated with submicroscopic chromosomal rearrangements detected by CGH microarray analysis. Eur J Med Genet 2012;55(10):527-30. PMID 22766001
127: Ramos JN, Soares P, Caetano A. Unilateral perirolandic polymicrogyria with ipsilateral brainstem hypoplasia and compensatory contralateral hyperplasia. Neurol Sci 2023;44(7):2617-9. PMID 36862200
128: Ravenscroft G, Di Donato N, Hahn G, et al. Recurrent de novo BICD2 mutation associated with arthrygryposis multiplex congenita and bilateral perisylvian polymicrogyria. Neuromusc Disord 2016;26(11):744-8. PMID 27751653
129: Riccardi D, Lavorgna L, Cirillo G, et al. Unilateral polymicrogyria, hemispheric atrophy and spastic hemparesis: rare etiologies for a common condition. Acta Neurol Belg 2021;121(3):789-90. PMID 33151517
130: Righini A, Zirpoli S, Mrakic F, et al. Early prenatal MR imaging diagnosis of polymicrogyria. Am J Neuroradiol 2004;25(2):343-6. PMID 14970044
131: Robin NH, Taylor CJ, McDonald-McGinn DM, et al. Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation. Am J Med Genet A 2006;140(22):2416-25. PMID 17036343
132: Roh CH, Kim DS, Lo GW, et al. Motor organization of unilateral polymicrogyria associated with ipsilateral brainstem atrophy – a case report. BMC Neurol 2022;22(1):303. PMID 35982397
133: Romaniello R, Arrigoni F, Fry AE, et al. Tubulin genes and malformations of cortical development. Eur J Med Genet 2018;61(12):744-54. PMID 30016746
134: Romero DM, Bahi-Buisson N, Francis F. Genetics and mechanisms leading to human cortical malformations. Semin Cell Dev Biol 2018;76:33-75. PMID 28951247
135: Rondagh M, Groene SG, deVries LS, Lopriore E, Steggerda SJ. Congenital bilateral perisylvian polymicrogyria in twin-twin transfusion syndrome and selective fetal growth restriction. Neurology 2023;101(21):970-1. PMID 37648524
136: Rudzinski ER, Kapur RP, Hevner RF. Fetal akinesia deformation sequence with delayed skeletal muscle maturation and polymicrogyria: evidence for a hypoxic/ischemic pathogenesis. Pediatr Dev Pathol 2010;13(3):192-201. PMID 19968489
137: Sarma K, Nayak MK, Mishra B, Gaikwad SB. Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP): a rare dynamic genetic disorder. Cureus 2022;14(5):e25123. PMID 35733479
138: Sarnat HB, Flores-Sarnat L. Excitatory/inhibitory synaptic ratios help explain epileptogenesis in polymicrogyria and Down syndrome help explain epileptogenesis in malformations. Pediatr Neurol 2021;116:41-54. PMID 33450624
139: Sarnat HB. Proteoglycan (keratan sulfate) barrier in developing human forebrain isolates cortical epileptic networks from deep heterotopia, insulates axonal fascicles, and explains why axosomatic synapses are inhibitory. J Neuropathol Exp Neurol 2019;78(12):1147-59. PMID 31633782
140: Sarnat HB, Flores-Sarnat L. Telencephalic flexure and disorders of the lateral cerebral (Sylvian) fissure. Pediatr Neurol 2016;63:23-38. PMID 27590993
141: Sarnat HB, Hader W, Flores-Sarnat L, Bello-Espinosa L. Synaptic plexi of the U-fibre layer beneath focal cortical dysplasias: role in epileptic networks. Clin Neuropathol 2018;37(6):262-76. PMID 30232955
142: Sarnat HB, Philippart M, Flores-Sarnat L, Wei XC. Timing in neural development: arrest, delay, precociousness and temporal determination of malformations. Pediatr Neurol 2015;52(5):473-86. PMID 25797487
143: Sculier C, Taussig D, David O, et al. Focal polymicrogyria in children: contribution of invasive explorations and epileptogenicity mapping in the surgical decision. Seizure 2021;86:19-28. PMID 33517238
144: Sethi M, Pedersen M, Jackson GD. Polymicrogyric cortex may predispose to seizures via abnormal network topology: an fMRI connectomics study. Epilepsia 2016;57(3):e64-8. PMID 26763051
145: Shao DD, Achkar CM, Lai A, et al. Polymicrogyria is associated with pathogenic variants in PTEN. Ann Neurol 2020;88(6):1153-64. PMID 32959437
146: Shen J, Gilmore EC, Marshall CA, et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet 2010;42(3):245-9. PMID 20118933
147: Simister RJ, McLean MA, Barker GJ, Duncan JS. Proton magnetic resonance spectroscopy of malformations of cortical development causing epilepsy. Epilepsy Res 2007;74(2-3):107-15. PMID 17379481
148: Skucas AP, Artru AA. Anesthetic complications of awake craniotomies for epilepsy surgery. Anesth Analg 2006;102(3):882-7. PMID 16492845
149: Smith RS, Kenny CJ, Ganesh V, et al. Sodium channel SCN3A (Nav1.3) regulation of human cerebral cortical folding and oral motor development. Neuron 2018;99(5):905-13. PMID 30146301
150: Soriano SG, Bozza P. Anesthesia for epilepsy surgery in children. Childs Nerv Syst 2006;22(8):834-43. PMID 16786371
151: Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatr 2009;98(3):421-33. PMID 19120042
152: Squier W, Jansen A. Polymicrogyria: pathology, fetal origins and mechanisms. Acta Neuropathol Commun 2014;2:80.** PMID 25047116
153: Stutterd CA, Brock S, Stouffs K, et al. Genetic heterogeneity of polymicrogyria: study of 123 patients using deep sequencing. Brain Commun 2020a;3(1):fcaa221. PMID 33604570
154: Stutterd CA, Francis D, McGillivray G, Lockhart PJ, Leventer RJ. Polymicrogyria associated with 17p13.3p13.2 duplication: case report and review of the literature. Eur J Med Genet 2020b;63(4):103774. PMID 31585183
155: Stutterd CA, Leventer RJ. Polymicrogyria: a common and heterogeneous malformation of cortical development. Am J Med Genet C Semin Med Genet 2014;166C(2):227-39. PMID 24888723
156: Sztriha L, Guerrini R, Harding B, Stewart F, Chelloug N, Johansen JG. Clinical, MRI, and pathological features of polymicrogyria in chromosome 22q11 deletion syndrome. Am J Med Genet A 2004;127A(3):313-7. PMID 15150787
157: Takahashi A, Otsuki T, Honda R, Nakagawa E, Sugai K, Sasaki M. Resective surgery for intractable epilepsy due to malformations of cortical development in early infancy. No To Hattatsu 2013;45(3):206-10. PMID 23785835
158: Takashima S, Becker LE, Armstrong DL, Chan F. Abnormal neuronal development in the visual cortex of the human fetus and infant with Down’s syndrome: a quantitative and qualitative Golgi study. Brain Res 1981;225(1):1-21. PMID 6457667
159: Teixeira KC, Montenegro MA, Cendes F, Guimaraes CA, Guerreiro CA, Guerreiro MM. Clinical and electroencephalographic features of patients with polymicrogyria. J Clin Neurophysiol 2007;24(3):244-51. PMID 17545827
160: Ten Donkelaar HJ. Polymicrogyria: the common endpoint of many different aetiological processes. Dev Med Child Neurol 2016;58(1):7. PMID 26251133
161: Toldo I, Calderone M, Sartori S, et al. Bilateral perisylvian polymicrogyria with cerebellar dysplasia and ectopic neurohypophysis. J Child Neurol 2011;26(3):361-5. PMID 21273507
162: Verrotti A, Spalice A, Ursitti F, et al. New trends in neuronal migration disorders. Eur J Paediatr Neurol 2010;14(1):1-12. PMID 19264520
163: Vlachou V, Larsen L, Pavilidou E, et al. SCN2A mutation in an infant with Ohtahara syndrome and neuroimaging findings: expanding the phenotype of neuronal migration disorders. J Genet 2019;98(2);27. PMID 31204721
164: Wang DD, Knox R, Rolston JD, et al. Surgical management of medically refractory epilepsy in patients with polymicrogyria. Epilepsia 2016;57(1):151-61. PMID 26647903
165: White RJ, Wang Y, Tang P, Montezuma SR. Knobloch syndrome associated with polymicrogyria and early onset of retinal detachment: two case reports. BMC Ophthalmol 2017;17(1):214. PMID 29178892
166: Williams RS, Ferrante RJ, Caviness VS Jr. The cellular pathology of microgyria. A Golgi analysis. Acta Neuropathol (Berl) 1976;36(3):269-83. PMID 64105
167: Wu YW, Lindan CE, Henning LH, et al. Neuroimaging abnormalities in infants with congenital hemiparesis. Pediatr Neurol 2006;35(3):191-6. PMID 16939859
168: Yu TW, Mochida GH, Tischfield DJ, et al. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 2010;42(11):1015-20. PMID 20890278
169: Zaman T, Helbig I, Bozovic IB, et al. Mutations in SCN3A cause early infantile epileptic encephalopathy. Ann Neurol 2018;83(4):703-17. PMID 29466837
170: Zambonin JL, Dyment DA, Xi Y, et al. A novel mutation in LAMC3 associated with generalized polymicrogyria of the cortex and epilepsy. Neurogenetics 2018;19(1):61-5. PMID 29247375

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Harvey B Sarnat MD FRCPC MS

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.
See Profile

Former Authors

Dikran S Horoupian MD
Hannes Vogel MD
Mohanpal Singh Dulai MD
Luis E Bello-Espinosa MD

Patient Profile

Age range of presentation: 0 month to 44 years
Sex preponderance: male=female
Heredity: heredity may be a factor

autosomal dominant

autosomal recessive

X-linked

BFPP: 16q12.2-21

BGP: autosomal recessive

BPP: X-linked (Xq28), deletion 22q11.2, possible deletion 1p36
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Microgyria: Q04.3
ICD-11: Polymicrogyria: LA05.50
OMIM: Micropolygyria with muscular dystrophy: #253800

Polymicrogyria, bilateral frontoparietal: #606854

Polymicrogyria, bilateral perisylvian: #300388

Polymicrogyria, unilateral: #610031

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Polymicrogyria

Associated Disorders

Aicardi syndrome
Chiari I malformation
Cortical dysplasia
Foix-Chavany-Marie syndrome
Glioneuronal leptomeningeal heterotopia
- Glutaric academia type II
- Histidinemia
- Leigh syndrome
- Lissencephaly, types I and II
- Maple syrup urine disease
- Mitochondrial respiratory chain deficiency
- Neonatal adrenoleukodystrophy
- Nodular heterotopia
- Pachygyria
- Pelizaeus-Merzbacher disease
- Porencephaly
- Schizencephaly
- Spinal muscular atrophy in BICD2 mutation
- Thanatophoric dysplasia
- Twin to twin transfusion syndrome
- Walker-Warburg syndrome
- Zellweger syndrome

Differential Diagnosis

ulegyria
granular atrophy
polygyria
lissencephaly type II

Also Relevant

Congenital toxoplasmosis
Epilepsy
Focal cortical dysplasias
Hemimegalencephaly
Lissencephalies
- Maple syrup urine disease
- Porencephaly
- Schizencephaly

Polymicrogyria …

Polymicrogyria

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Norrie disease

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

Polymicrogyria

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Norrie disease

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

This is an article preview.
Start a Free Account
to access the full version.