How are Malformations of the Cerebral Cortex Grouped?

Patient Presentation
A 3-year-old male came to the inpatient floor because of intractable emesis of non-bilious fluid and stomach contents and some watery diarrhea for 36 hours after exposure to a particularly virulent form gastroenteritis at his daycare. He was not tolerating any oral or gastrotube feedings and had not urinated for 10 hours. He also had a 10-15 second generalized tonic-clonic seizure in the emergency room that was similar to his usual seizures that generally occurred 2-3 times/week. He also had a bout of watery diarrhea in the emergency room. The past medical history showed him known to have microcephaly with some areas of polymicrogyri diagnosed as an infant, and seizures that were reasonably well-controlled on phenytoin.

The pertinent physical exam showed a male in mild distress with dry mucous membranes. His weight was down 1040 grams from a recent clinic visit. His heart rate was 112 beats/minute and respirations were 26/minute. His blood pressure was 76/54. His abdomen was very mildly tender diffusely without guarding or rebound tenderness. His gastric tube was in place. There was no organomegaly and his bowel sounds were hyperactive. Neurologically he was semi-noncommunicative. His cranial nerves were normal, DTRs were slightly hyperreflexic and his tone was good. This was his normal neurological examination and the rest of his examination was normal. The work-up showed a normal abdominal radiograph, electrolytes and urinalysis were consistent with mild dehydration, and his complete blood count was normal. His phenytoin level was therapeutic. The diagnosis of gastroenteritis and dehydration was made. In the emergency room he was given ondansteron and intravenous fluids but he still could not tolerate fluids and was admitted. Over the next 24 hours he began to tolerate fluids. He had another similar seizure but again had therapeutic levels and his parents and neurologist were comfortable monitoring him at home and potentially making medication changes by telephone.

Discussion
Cerebral cortex development is an extremely complex process overall. Our current understanding is incomplete and constantly changing as our understanding of genetics and the processes each gene controls emerges from scientific research.
Neural cells are produced in the subventicular zone of the pallial or dorsal germinal epithelium. They then differentiate and migrate radially or tangentially to the cerebral cortex and organize themselves to function.

Malformations of cortical development (MCD) is a heterogeneneous group of disorders that cause defective cortical development. These disorders are broadly categorized into three areas of cerebral cortical development: neural cell proliferation, neural cell migration and cortical organization. There is wide variation in the radiographic features and clinical problems seen and individuals may have more than one of these broad classifications (i.e. have elements 1 or all 3 classifications such as polymicrogyri). Additionally, the brain may be affected with these malformations globally or focally (focal cortical development). Specific wording and classifications for MCDs are necessarily changing as more information is learned.

Malformations of cortical development presenting signs and prognosis predictors are shown in this table, modified from Guerrini and Dobyns (see To Learn More below). MCDs that are more global or that are due to neural cell proliferation problems are often more severe.

Characteristic Most Severe Intermediate Less Severe
MCD distribution Diffuse Frontal-perisylvian Posterior or other
MCD symmetry Bilateral symmetrical Bilateral asymmetrical Unilateral
Head Size Microcephaly Megalencephaly Normal head size
Tone Spascity Hypotonia Normal
Seizure Onset Early, 0-3 months Infancy, 3-12 months Late, > 12 months
Seizure Type Early infantile epileptic encephalopathy,
Infantile spasms,
Lennox-Gastaut syndrome
Non-specific generalized Focal, other types

Learning Point

  • Neural cell proliferation
    • Neural cells need to proliferate, grow and differentiate. Neural cells can divide symmetrically to expand their numbers or asymmetrically to self-renew or generate progenitor cells.
      • Examples:
        • Microcephaly
          • Microcephaly vera or true microcephaly is due to MCD problem, not due to damage or atrophy. It is a small head usually < 2 S.D. for gender and age.
            A review of cases of microcephaly can be found here. This includes non-MCD causes.
        • Megalencephaly
          • A large head usually defined as > 2 S.D. for gender and age (some people are more restrictive as benign familial macrocephaly may be > 2 S.D.) which is caused by too many neural cells.
            “Megalencephaly is different from macrocephaly (also called megacephaly or megalocephaly), which describes a big head, and which doesn’t necessarily indicate abnormality.”
        • Cortical dysgenesis
          • These can be more focal as in focal cortical dysgenesis or hemimegalencephaly where atypical gyri are seen in 1 or more locations
  • Neural cell migration
      Cellular movement is obviously complex involving nuclear and microtubule transport at the cellular level and other processes to direct and allow migration to the cortex. Neural cells can undermigrate, overmigrate or have migration defects.

        Examples:

        • Lissencephaly
          • Classically an undermigration problem, usually seen with a grossly smooth brain surface, can affect 1 or several layers of the cortex
        • Pachygyri
          • Usually an undermigration problem where there are few or large gyri grossly
        • Heterotopia
          • Groups of neurons in abnormal locations
            • Periventricular nodular heterotopia
            • Subcortical heterotopia – sometimes known as double cortex syndrome
          • Cobblestoning malformation
            • Polymicrogyri – see below
  • Cortical organization
    • Neurons that arrive at the proper location must then organize to work together to perform the appropriate tasks and link with other neuronal structures. This is done through folding and maturational changes.
    • Examples:
      • Polymicrogyri
        • Overmigration problem that appears to look like cobblestones or pebbles, can be associated with megancephaly, maybe related to lissencephaly
      • Schizencephaly
        • Cleft in the brain wall from the ventricle to the surface potentially genetic but also thought to be caused by intrauterine injury similar to porencephaly (or cysts/cavities within the brain result from intrauterine injuries such as strokes). The walls of the cleft are lined with polymicrogyri.

Questions for Further Discussion
1. What are causes of macrocephaly?
2. What are the clinical phenotypes caused by Zika virus?
3. What are the classifications of seizures? A review can be found here.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for these topics: Dehydration and Brain Malformations.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Squier W, Jansen A. Abnormal development of the human cerebral cortex. J Anat. 2010 Oct;217(4):312-23.

Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012.
Brain. 2012 May;135(Pt 5):1348-69.

Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014 Jul;13(7):710-26.

National Institute of Neurological Disorders and Stroke. Megalencephaly Information Page.
Available from the Internet at https://www.ninds.nih.gov/Disorders/All-Disorders/Megalencephaly-Information-Page (rev. 5/25/17, cited 5/29/18).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa