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  • Updated 05.26.2021
  • Released 05.31.2000
  • Expires For CME 05.26.2024

Periventricular nodular heterotopia



Periventricular nodular heterotopia is a malformation of cortical development due to impaired neuronal migration. Neurologists should become familiar with this brain malformation because periventricular nodular heterotopia are among the most frequent brain dysgenesis encountered in clinical practice and affected patients are frequently characterized by focal, drug-resistant epilepsy, varying degrees of cognitive impairment, as well as extracerebral findings. In this article, the author provides an update on the topic, including the expanding clinical and genetic spectrum, neurophysiological investigations, and current management options, including epilepsy surgery.

Key points

• Periventricular nodular heterotopia can be: (1) bilateral and symmetrical, (2) bilateral single-noduled, (3) bilateral and asymmetrical, (4) unilateral, or (5) unilateral with extension to neocortex.

• It is likely that genetic factors play a more important role in the bilaterally, as opposed to unilaterally, affected cases.

• Epilepsy is the most common symptom (in 80% to 100% of reported cases).

• Developmental delay and cognitive issues are more common in the pediatric population.

• Surgery outcome may be good, with resections limited to the periventricular nodules, cortex, or both after functional studies and proper invasive EEG assessment of the epileptogenic areas.

Historical note and terminology

During the embryonic development of the brain, neuroblasts migrate away from the germinal layer of the ventricular neuroepithelium, mainly along the tracks of radial glial fibers, which stretch from the ventricular zone to the external pial surface of the developing brain. Any impairment of the complex processes underlying neuronal migration may determine the presence of clusters of abnormally located neurons (eg, gray matter heterotopia) (13).

According to classic neuropathologic studies, 2 types of heterotopia can be distinguished: laminar and nodular (65). Laminar heterotopia is organized in laminar bands of neurons interposed between the cortex and the lateral ventricles. This is now termed "band heterotopia," according to MRI studies (10). Nodular heterotopia is characterized by the periventricular location of the heterotopic neurons close to the subependymal germinal matrix. For this reason, this is usually referred to as "periventricular nodular heterotopia." Periventricular nodular heterotopia is made up of round nodular masses of normal neurons and glial cells with no laminar organization, which cause bulging of the ventricular walls. They can be diagnosed in vivo by means of neuroimaging (11; 09), and they are, together with focal cortical dysplasia, the most common forms of human brain dysgenesis.

Patients affected by periventricular nodular heterotopia have been classified on the basis of MRI features (12). Five different groups of periventricular nodular heterotopia have been distinguished (16): (1) bilateral and symmetrical; (2) bilateral single-noduled; (3) bilateral and asymmetrical; (4) unilateral; and (5) unilateral with extension to neocortex. It is likely that genetic factors play a major role in the bilaterally affected patients. In particular, bilateral and symmetrical cases are characterized by a clear female predominance, positive family history for epilepsy, and familial occurrence (49). They have been identified as an X-linked dominant disease with linkage mapping to chromosome Xq28, determined by mutations of the filamin A or filamin1 gene (FLNA or FLN1), a gene originally isolated from blood cells (63). A multicentric study analyzed the filamin A gene in a large number of patients, revealing FLNA mutations in patients with bilateral and symmetrical periventricular nodular heterotopia, associated with Ehlers-Danlos syndrome in a few cases (128). Several other causative genes have been described for periventricular nodular heterotopia and will be discussed in this review. Unilateral periventricular nodular heterotopia, on the other hand, is not usually associated with preferential sex prevalence, familial occurrence, or FLNA mutations. Therefore, unilateral cases are most probably determined by vascular mechanisms that may impair in utero the perfusion of a limited part of the developing brain. In addition, a malformation complex has been described with periventricular nodular heterotopia in the trigones and the occipitotemporal horn associated with hippocampal, corpus callosum, and cerebellar dysgenesis (130).

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