What is polymicrogyria?

What is Polymicrogyria

Polymicrogyria is a malformation of cortical development characterized by an excessive number of abnormally small cerebral gyri with cortical overfolding, an irregular "pebbled" cortical surface, and a distinctive "stippled" gray-white matter junction. 1

Core Definition and Pathological Features

Polymicrogyria represents one of the most common and heterogeneous cortical malformations, microscopically defined by excessive folding of the cortical mantle resulting in small gyri with a fused surface. 1, 2 The condition involves abnormal cortical lamination that distinguishes it from normal brain architecture. 3

Anatomical Distribution Patterns

The malformation can present in several distinct patterns:

• Perisylvian involvement is most common (60-70% of cases), particularly affecting the posterior aspect of the Sylvian fissures, which often show abnormal posterior and superior extension with abnormal branching sulci. 1, 4

• Distribution may be focal, multifocal, or generalized, and can occur unilaterally or bilaterally (symmetric or asymmetric). 1

• Any cortical region can be affected, including frontal, parietal, temporal, and occipital lobes, though perisylvian regions predominate. 1

• In large cohort studies, the distribution breaks down as: perisylvian (61%), generalized (13%), frontal (5%), and parasagittal parieto-occipital (3%), with 11% showing associated periventricular heterotopia. 4

Imaging Characteristics and Diagnostic Challenges

The appearance of polymicrogyria varies significantly on MRI depending on myelination stage and technical factors, which creates diagnostic complexity:

• In the unmyelinated brain, polymicrogyria appears as a thin, bumpy or "stippled" gray-white junction (2-3 mm thick). 1

• In the myelinated brain, the same cortex evolves to appear thicker and relatively smooth (5-8 mm), potentially mimicking pachygyria despite completely different pathophysiology. 1

• The cortical surface may show multiple small delicate gyri, thick irregularly bumpy "palisades" of cortex, or paradoxically smooth appearance when the outer cortical layer fuses over microsulci. 1, 5

• Unlike lissencephaly, the cortex is never truly thick but is overfolded, though it may appear thickened on imaging due to a 4-5 mm layer of gliotic white matter running through the polymicrogyric cortex. 1

Etiology: Genetic and Non-Genetic Causes

Polymicrogyria has a highly heterogeneous etiology requiring systematic evaluation:

Genetic Causes

• Chromosomal abnormalities including 22q11 deletions and 1p36 monosomy. 1
• Single gene mutations in COL4A1/COL4A2, OCLN, RTTN, GRIN1, GPR56, and ATP1A2. 1, 5, 3, 2
• Submicroscopic chromosomal rearrangements detectable by chromosomal microarray analysis, even in focal or unilateral forms. 6

Non-Genetic (Clastic) Causes

• In utero infections, primarily CMV or Zika virus. 1
• Vascular insults including arterial ischemic infarcts and twin-to-twin transfusion syndrome or death of a monozygotic twin. 1
• Teratogen exposure, particularly alcohol. 1
• Trauma during fetal development. 1

In non-genetic cases, pathological specimens demonstrate injury to the distal radial glia, pia, or arachnoid. 1, 5

Pathophysiological Mechanisms

Multiple mechanisms contribute to polymicrogyria formation:

• Premature folding of the neuronal band. 1
• Abnormal fusion of adjacent gyri. 1
• Laminar necrosis of the developing cortex. 1
• Altered physical properties of thickened leptomeninges exerting mechanical constraints on the developing cortex. 1
• Gaps in the pial limiting membrane allowing neuronal migration into subarachnoid space (small gaps produce polymicrogyria; large gaps produce cobblestone malformation). 1

Clinical Manifestations

The clinical spectrum is broad and severity correlates with extent of involvement:

• Epileptic seizures occur in 78% of patients, with earlier onset in generalized and bilateral forms. 4
• Global developmental delay affects 70% of patients. 4
• Spasticity occurs in 51% and microcephaly in 50%. 4
• Additional features include dysconjugate gaze, bilateral pyramidal and cerebellar signs, and speech disturbances. 7, 4

Patients with more extensive patterns present earlier (median age 4 months for entire cohort, with 38% presenting antenatally or neonatally) and have more severe sequelae than those with restricted or unilateral forms. 4

Important Clinical Pitfalls

• Many patients present with neurological or developmental abnormalities before epilepsy onset, so absence of seizures should not exclude the diagnosis. 4
• Polymicrogyria may be misdiagnosed as other malformations due to variable imaging appearance; bilateral frontoparietal polymicrogyria is frequently misclassified. 7
• The condition shows male predominance with a 3:2 ratio. 4
• Even focal, unilateral, or isolated forms warrant chromosomal microarray screening for submicroscopic rearrangements. 6