Dr. Nelson of Tulane University School of Medicine received consulting fees from BioMarin and Supernus for speaking engagements.)
Dr. Johnston of Johns Hopkins University School of Medicine and Chief Medical Officer at Kennedy Krieger Institute has no relevant financial relationships to disclose.)
This article includes discussion of megalencephaly, benign enlargement of subarachnoid spaces of infancy, benign familial macrocephaly, familial anatomic megalencephaly, symptomatic megalencephaly, anatomic megalencephaly, benign familial megalencephaly, clinically insignificant megalencephaly, clinically significant megalencephaly, metabolic megalencephaly, primary macrencephaly, and primary megalencephaly. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The author reviews the various anatomic and metabolic causes of megalencephaly. Macrocephaly refers to an enlarged occipital-frontal circumference statistically greater than 2 standard deviations above the mean for age and sex due to any etiology (such as excess fluid, thickened skull, brain abnormality, or clinically “normal” statistical outlier). In contrast, megalencephaly refers to a large brain, which can be due to either anatomic or metabolic reasons. Thus, individuals with macrocephaly may or may not have megalencephaly. Megalencephaly falls on a spectrum from clinically significant to apparently clinically insignificant. This article discusses information on megalencephaly, including a review of the recent literature.
• Megalencephaly can be due to either anatomic or metabolic etiologies, and both can range from clinically insignificant to significant.
• The most common cause of megalencephaly is benign familial megalencephaly, which is usually associated with a good outcome and runs in families.
• There are a large number of genetic syndromes and metabolic disorders associated with megalencephaly; thus, a careful neurologic and physical exam is required in all children presenting with megalencephaly.
• Although all individuals with megalencephaly will have macrocephaly, the reverse is not true because large heads can result from an excessive amount of fluid, abnormally large brain size, or increased skull bone thickness.
Historical note and terminology
The terms megalencephaly and macrencephaly have traditionally been used to describe individuals with large heads. However, macrocephaly implies an occipital-frontal circumference of greater than 2 standard deviations above the mean for age and sex but does not specify whether the enlargement is due to excessive brain, fluid, or skull thickness, whereas megalencephaly is defined as “an oversized and overweight brain.” The terminology has been the subject of much discussion over the years, with the availability of modern imaging techniques allowing these individuals to reliably be distinguished. Furthermore, the differential diagnosis of megalencephalic individuals has greatly expanded with delineation of more disorders and syndromes associated with megalencephaly.
Though Virchow used the term "kephalonen" in 1857 to describe patients with cerebral hyperplasia, Fletcher in 1900 first used the term “megalencephaly” (Virchow 1857; Fletcher 1900). Wilson in 1934 provided an early literature review as well as some original cases demonstrating that although some individuals with large brains functioned with superior intellect, many had some degree of neurologic impairment (Wilson 1934).
The importance of clear terminology has become increasingly evident as “large-brained” individuals do not easily, or at least initially, dichotomize into neurologically “normal” and “abnormal” groups. As knowledge of various causes of macrocephaly and the number of associations with megalencephaly grew, confusing use of terminology increased. By the 1960s, authors realized the increasing need for appropriate use of terms when describing any enlargement of the head.
“Macrocephaly” refers to a large head of any etiology (eg, hydrocephalus, skeletal anomaly, brain abnormality, or a “normal” statistical outlier) whereas megalencephaly refers to individuals with abnormally large heads accompanied by “heavy” brains, implying abnormal structure or function (Laurence 1964b).
Subclassification of megalencephalic individuals has been challenging and continually changing due to the increasingly large number of diverse etiologies that may be associated with megalencephaly. DeMyer proposed an initial division into 2 groups (DeMyer 1972; DeMyer 1986). Anatomic megalencephaly included individuals whose brains were enlarged secondary to increases in the size or number of cells without associated storage of abnormal metabolic products. Metabolic megalencephaly identified those that resulted from the abnormal accumulation of metabolic substances within the cells of the brain leading to its enlargement. These 2 groups, however, have proven to be heterogeneous.
Later attempts to differentiate individuals with megalencephaly by adding the terms “primary” or “secondary” proved somewhat frustrating due to marked phenotypic variability within groups. An additional category was created to allow for unilateral megalencephaly (Laurence 1964a; Dekaban and Sakuragawa 1977).
Other patients who are difficult to categorize are those diagnosed with “benign extra-axial fluid collections,” “idiopathic external hydrocephalus,” or “extraventricular obstructive hydrocephalus.” A disturbance in CSF dynamics continues to be debated as a possible etiology. Gooskens and colleagues suggested a return to DeMyer's anatomic and metabolic divisions of megalencephaly with the addition of a third group, the "dynamic megalencephalies," in order to include these individuals (Gooskens et al 1988b). These extracerebral fluid collections can contribute to macrocephaly (most commonly “benign enlargement of the subarachnoid spaces of infancy”) in children and are now considered related to benign familial macrocephaly; given that as adults the excess fluid usually resolves, with resultant increased brain size and mass, many of these individuals can also be classified with benign familial megalencephaly as adults (see Extracerebral fluid collections in infants summary) (Frim and Curry 2008; Fenichel 2009).
Megalencephaly will be approached in this summary as most frequently categorized: anatomic and metabolic (Winden et al 2015). Both of these categories will include patients with either clinically significant or insignificant megalencephaly, depending on the underlying etiology and the current stage of that underlying etiology.
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