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Polymicrogyria

What is Polymicrogyria?

Polymicrogyria

Axial FSE T2 weighted image shows right frontal PMG (white arrows) with fusion of the molecular layer of cortex resulting in paradoxically smooth cortical surface.

Polymicrogyria (PMG) is a cortical malformation characterized by an excessive number of small, partly fused, convolutions (gyri) on the surface of the brain. The Greek roots of the name describe its salient features:  poly (many) micro (small) gyria (folds in the brain). PMG is a malformation of cortical development in which the process of normal cerebral cortical development is disturbed late in the stage of neuronal migration or early in the stage of cortical organization and is considered a disorder of “post migration”. PMG can appear as either a focal lesion or a more widespread cortical abnormality and is often seen in association with other cortical malformations like schizencephaly or heterotopia.  PMG is also associated with a number of genetically determined syndromes; including Zellweger syndrome, Aicardi syndrome, and Walker-Warburg syndrome.

Characteristics

As a result of disturbances in the development process, the deeper layers of the cerebral cortex develop abnormally and small gyri form within the cortex. PMG has a range of appearances, all having in common a derangement of the normal six-layered lamination of the cortex, an associated derangement of sulcation, and fusion of the molecular layer across sulci. In areas of PMG, no normal sulci are seen.

PMG may affect a variety of areas in the cortex:  it may be focal, multifocal, or diffuse. It may be unilateral, bilateral, and asymmetrical; or bilateral and symmetrical. Approximately 40% of cases are unilateral and 60% of cases are bilateral. The most common location (in 60-70% of cases) is around the sylvian fissure, particularly the posterior area of the fissure; however, any part of the cerebral cortex can be affected, including the frontal (~70%), occipital (~7%), and temporal lobes (38%), can be affected.

Bilateral perisylvian PMG (congenital bilateral perisylvian syndrome) consists of primitive Sylvian fissures, primitive draining veins, and dysplastic operculum. It may be sporadic or familial. It usually presents with pseudobulbar palsy, epilepsy, cognitive impairment, and congenital arthrogryposes. On MR imaging, the Sylvian fissures are wide, deep, and underdeveloped and extend farther back. An anomalous vein is seen in the unfolding dysplastic cortex. The opercula are dysplastic due to symmetric involvement with PMG and pachygyria. It may be seen in families linked to the locus on Xq28.

Polymicrogyria

Image shows course PMG in the parieto-occipital (small black arrows) and perisylvian (large black arrows) regions

Bilateral frontal PMG presents with cognitive and motor delay and spastic quadriparesis with epilepsy. There is symmetric PMG extending from the frontal poles posteriorly to the precentral gyrus and inferiorly to the frontal operculum. All cases are sporadic and patients may have consanguineous parents.

Bilateral frontoparietal PMG is commonly seen in the Middle East and India. Patients present with developmental delay, mild spastic quadriparesis, impaired language, and epilepsy with cerebellar dysfunction. There is characteristic bilateral symmetric PMG in the frontoparietal regions, with decreased severity anteriorly to posteriorly. The white matter is thin, with areas of T2 prolongation. The ventricles are enlarged, and the pons and cerebellum are small. It is autosomal recessive, with the locus identified on 16q12.2.

Bilateral parasagittal parieto-occipital PMG presents with seizures and intellectual disabilities; however, neurologic deficits are often absent. Bilateral PMG is seen in the parasagittal and mesial aspects of the parietooccipital cortex. All cases are sporadic.

Bilateral generalized PMG presents with cognitive and motor delay of variable severity with seizures. There is symmetric generalized PMG, often most prominent in perisylvian regions. Most cases are presumed to be autosomal recessive.

Polymicrogyria

Bilateral perisylvian polymicrogyria (BPP)

Classification and known presentations

PMG may be classified according to severity on MRI (with Grade 1 the most severe and Grade 4 the mildest). Grade 1, with perisylvian PMG extending to the frontal or occipital pole; Grade 2, with PMG extending beyond the perisylvian region but not to either pole (most common); Grade 3, with PMG of the perisylvian region only; and Grade 4, with PMG restricted to the posterior perisylvian regions.  There are 45 types of PMG:

PMG with Microcephaly (MIC)

Clinically defined with AR or XL inheritance

  • MIC with diffuse PMG
  • MIC with asymmetric PMG

Genetically defined with AR inheritance

PMG with Megalencephaly (MEG)

Clinically defined with unknown cause

  • MEG with PMG and other cortical dysgenesis

PMG with Periventricular nodular heterotopia (PNH)

Polymicrogyria

Bilateral perisylvian polymicrogyria. T1-weighted axial section showing open sylvian fissures overlaid by an irregular and thick cortex. A sixteen-year-old male patient with facio-pharingo-glosso-masticatory diplegia, mild mental retardation and Lennox-Gastaut syndrome.

Clinically defined with unknown cause

PMG with Subcortical heterotopia (other than band heterotopia)

Clinically defined with unknown cause

  • Multinodular subcortical heterotopia with thin overlying cortex, with/without PMG (Barkovich, 2000)

PMG (classic) with transmantle clefts (schizenzephaly) or calcification

Clinically defined with prenatal viral exposure

  • Diffuse or patchy PMG with periventricular calcifications and positive neonatal CMV testing
  • Diffuse, patchy or perisylvian PMG with hearing loss and positive neonatal CMV testing

Clinically defined with AR inheritance

Genetically defined with AR inheritance

PMG without clefts or calcifications, classified by location

Polymicrogyria

Bilateral parasagittal parieto-occipital polymicrogyria. T1-weighted MRI showing irregular thickening and infolding of the cortex at the mesial parieto-occipital junction.

Clinically defined bilateral PMG without clefts of unknown cause

Clinically defined unilateral PMG without clefts of unknown cause

Syndromes with PMG (neuropathology may differ from classic PMG)

Clinically defined syndromes with AD inheritance

Clinically defined syndromes with AR inheritance

  • Adams–Oliver syndrome AR form (Snape et al., 2009)
  • Joubert syndrome and related disorders with PMG, includes Meckel–Gruber, Arima (cerebro-oculo-renal) and Joubert syndromes with causative genes unknown (Gleeson et al., 2004)

Clinically defined syndromes with XL inheritance (probable)

Genetically defined with AD inheritance (new mutations)

  • Polymicrogyria

    Bilateral frontal polymicrogyria. MRI, T1-weighted axial section. Polymicrogyric cortex with a irregular, bumpy aspect involves all the gyral pattern anterior to the precentral gyri. A 10-year-old boy with spastic quadriparesis, moderate mental retardation and partial epilepsy. Seizures have been in remission for some years.

    Fronto-parietal PMG, variable ACC and delayed myelination of anterior limb internal capsule with TUBB2B mutations at 6p25.2 (Jaglin et al., 2009)
  • Fronto-parietal PMG, variable with TUBB3 mutations at 16q24.3 (Poirier et al., 2010)
  • Knobloch syndrome with high myopia, vitreoretinal degeneration, retinal detachment, occipital cephalocele and variable PMG with COL18A1 mutations at 21q22.3 (Sertié et al., 2000)
  • Aniridia, variable temporal PMG, absent anterior commissure and pineal gland, and variable CBLH with PAX6mutations at 11p13 (Mitchell et al., 2003Graziano et al., 2007)
  • Perisylvian PMG with deletion 1p36.3 (gene not identified) (Dobyns et al., 2008)
  • Perisylvian PMG with deletion 22q11.2 (gene not identified) (Cramer et al., 1996)

Genetically defined with AR inheritance

Genetically defined with XL inheritance

Symptoms

Polymicrogyria

Unilateral polymicrogyria. MRI, T1-weighted axial section. The right hemisphere is smaller than the left and the subarachnoid space overlying the right hemisphere is enlarged. The cortex on the right is irregular, with areas of thickening. An eight year-old boy with left hemiparesis, moderate mental retardation, atypical absences and partial motor seizures.

Global development disabilities, mild to severe intellectual disabilities, motor dysfunction including speech and swallowing problems, weakness in the limbs (hemiparesis or quadriparesis), respiratory problems, and seizures (including intractable seizures). Though each case is unique, there are some generalized clinical findings based of the affected area of the brain:

  • Unilateral focal polymicrogyria – The mildest form of PMG.  May have minimal neurological manifestations.
  • Bilateral frontal polymicrogyria (BFP) – Cognitive and motor delay, spastic quadriparesis, epilepsy
  • Bilateral frontoparietal polymicrogyria (BFPP) – Severe cognitive and motor delay, seizures, dysconjugate gaze, cerebellar dysfunction
  • Bilateral perisylvian polymicrogyria (BPP) – Pseudobulbar signs, cognitive impairment, epilepsy, some with arthrogryposis and/or lower motor neuron disease
  • Bilateral parasagittal parieto-occipital polymicrogyria (BPPP) – Partial seizures, some with cognitive delays
  • Bilateral generalized polymicrogyria (BGP) – Severe intellectual disability, cerebral palsy, and refractory epilepsy may be present.

Diagnosis

PMG is typically diagnosed by MRI and/or CT scan. The imaging appearance of PMG is variable. The variability is most likely a result of three factors: imaging factors (amount of gray matter-white matter contrast, thickness of slices); the stages of maturity/myelination of the brain at the time of the imaging study; and, in all likelihood, the type of PMG2. It is commonly misdiagnosed as pachygyria (a form of lissencephaly), even by experienced radiologists, since the subtle differences can be difficult to detect on an MRI or CT scan. Variations in appearance may be difficult to detect on routine, 5-mm thick images. Thinner (1.5-mm or smaller) sections are optimal. Evaluation in all three planes (sagittal, axial, and coronal) is often necessary to detect irregularities of the grey matter-white matter junction, which are most often the most convincing evidence of abnormal brain development.  The cerebral cortex often appears abnormally thick as well because multiple small gyri are fused, infolded, and superimposed in appearance.  In actuality, the cerebral cortex is abnormally thin and has abnormal lamination; typically the cortex is unlayered or has four layers, in contrast to the normal six layers.

Cause

Known causes of PMG are genetic, viral (particularly cytomegalovirus), or in utero ischemia. The genes associated with polymicrogyria include: SRPX2 (Xq21.33-q23), RAB3GAP1 (2q21.3), EOMES (3p21.3-p21.2), TUBB2B (6p25), K1AA1279 (10q22.1), PAX6 (11p13), COL18A1 (21q22.3), and multiple genes located at 22q11.2. Bilateral perisylvian PMG (BPP) is due to mutations of SPRX2. A form of bilateral frontoparietal PMG (BFPP) is associated with GPR56 and resembles cobblestone lissencephaly. The neuropathology of genetic forms of PMG is not well defined. For the majority of individuals, an underlying cause for PMG cannot be identified, although exact figures are unknown.

Treatment

Treatment is symptomatic and may include:  physical therapy (including aqua therapy), occupational therapy for fine motor difficulties, speech therapy for language impairment, orthotic devices, antiepileptic medications for seizures, and assessment of educational needs and evaluations for speech, vision, and hearing difficulties in infancy and preschool years. For individuals with cerebral palsy, measures to prevent joint contractures and bedsores.

Prognosis

Individuals with milder forms of PMG survive into adulthood, while those with the most severe forms may die at a young age as a result of complications from seizures or pneumonia.

Prevalence

PMG is one of the most common malformations of cortical development. It has been known for many years and its clinical and MRI manifestations are well described. Bilateral perisylvian polymicrogyria (BPP) is the most commonly described syndrome; its prevalence, like that of the other syndromes with PMG, remains unknown.

Additional Resources

Other Organizations

Sources

  1. Guerini R, Dobyns WB, Barkovich AJ. “Abnormal development of the human cerebral cortex: genetics, functional consequences and treatment options”. Trends Neurosci. 2008 Mar; 31 (3): 154-62. PMID: 18262290.
  2. Barkovich, James A. “Current concepts of polymicrogyria”. Neuroradiology (2010) 52: 479-487.
  3. Leventer R (2007). “Polymicrogyria and related disorders of cortical development: a clinical, imaging, and genetic study”. In: Child Health Institute. Melbourne, Australia: University of Melbourne. 411.
  4. Jansen, A. Andermann, E. (2005). “Genetics of the polymicrogyria syndromes”. J Med Genet. 42: 369-378.
  5. GeneReviews, “Polymicrogyria Overview”, NCBI Bookshelf.
  6. Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. “A developmental and genetic classification for malformations of cortical development:  update 2012. Brain 2012. 10.1093/brain/aws019.