Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
Aug. 24, 2021
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This article includes discussion of agenesis of the corpus callosum, callosal agenesis, agenesis of the corpus callosum, hypoplasia of the corpus callosum, and agenesis and hypoplasia of the corpus callosum. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Agenesis of the corpus callosum may occur as an isolated event or as part of dozens of developmental and dysmorphic syndromes. Although affected patients may exhibit few obvious neurologic functional deficits, the absence of the corpus callosum, a structure responsible for interhemispheric connections, does carry consequences with respect to information processing and language functions. In this article, the author discusses attempts to classify and characterize agenesis of the corpus callosum based on morphologic and molecular findings.
• In patients with primary or isolated agenesis of the corpus callosum, the intelligence quotient (IQ) may be normal, but impaired processing between the hemispheres can be demonstrated by detailed psychometric testing and may manifest as deficits in learning and recall; associations with autism spectrum disorder have been studied.
• In cases where agenesis of the corpus callosum occurs as part of a syndrome or larger malformative cluster, the clinical scenario is usually dominated by the primary condition.
• Hypertelorism is the most common recognizable facial abnormality in patients with agenesis of the corpus callosum who have abnormal facial features.
• Hypoplasia of the corpus callosum exists when all the components of the callosum are present, but the structure is thinner than normal. This represents a global defect of brain development, whereas agenesis of the corpus callosum may be an isolated abnormality.
• Agenesis of the corpus callosum can be diagnosed or suspected in the antenatal period based on axial view ultrasound findings; further MRI studies may be able to further define anatomic abnormalities.
• Many genetic alterations have been etiologically linked to agenesis of the corpus callosum, both as isolated developmental events as well as in the context of syndromic clusters.
The corpus callosum, the largest fiber tract in the brain, connects to the 2 cerebral hemispheres in order to facilitate the integration of motor and sensory information from the 2 sides of the body. Agenesis of the corpus callosum has been recognized pathologically for over 160 years, and descriptions of the various clinical manifestations continue to accumulate (59). Studies on the behavioral aspects of this condition have been reported since 1912 (43; 31).
The recognition and diagnosis of agenesis of the corpus callosum in the living patient, however, was not possible with any degree of certainty until the development of pneumoencephalography in the early part of the 20th century (24). Newer neuroimaging techniques used to demonstrate agenesis of the corpus callosum include cranial ultrasonography, CT, and MRI. With the advent of even newer MRI techniques such as diffusion tensor imaging and tractography (74), the recognition of various forms of partial agenesis and hypoplasia of the corpus callosum has also become possible (09; 67). With additional experience and refinement of radiographic techniques, agenesis of the corpus callosum can now generally be confidently made, or at least highly suspected on fetal sonography, especially when interpreted in conjunction with MRI (63; 72).
The term "agenesis of the corpus callosum" is as old as the early pathologic descriptions. The use of the term "partial agenesis of the corpus callosum" is relatively new to the clinical literature, and the delineation of the diagnostic criteria for "hypoplasia" of the corpus callosum has only recently been accomplished concurrent with the use of computer-assisted analysis of MRI images (69).
Agenesis of the corpus callosum may be recognized antenatally or postnatally and may be partial or complete. This entity may occur as the sole neuropathologic finding, referred to as primary (or isolated) agenesis of the corpus callosum, or in association with other congenital abnormalities as part of a syndromic spectrum. In addition, as a malformative lesion of cortical development, agenesis of the corpus callosum may give rise to subtle clinical signs and symptoms, or exhibit numerous neurologic manifestations. The most frequent manifestation, however, is to encounter agenesis of the corpus callosum in association with other malformative lesions of the nervous system, and, to a lesser extent, accompanied by abnormalities in other organs (59; 49). The clinical neurologic manifestations of agenesis of the corpus callosum depend more on the degree of developmental abnormalities within the brain and midline structures than on the absence of the corpus callosum itself.
The features most commonly seen in patients with agenesis of the corpus callosum or hypoplasia of the corpus callosum are microcephaly, macrocephaly, seizures, developmental delay or retardation, hypotonia, and multiple somatic anomalies including arthrogryposis, eye anomalies, and facial dysmorphisms (17; 14; 71; 70). Although only one quarter of these children will have midline facial anomalies, this is the single most frequent category of somatic malformation (59). Hypertelorism is common, rather than midfacial hypoplasia with hypotelorism, as is seen in holoprosencephaly. Hypotonia is the most common abnormality of muscle tone, usually with reflexes depressed in proportion to the degree of hypotonia, though a small number of patients will have apparent corticospinal tract involvement and may even be spastic (68). Other described conditions associated with corpus callosal agenesis include corneal dystrophy and skeletal deformities (03; 32). Elgamal and colleagues described a population of patients with spinal open neural tube defects in which 45.8% had agenesis of the corpus callosum (26). Ocular albinism and cleft lip and palate accompanied by hypertelorism have also been described in isolated cases (07; 50).
The neonate with agenesis of the corpus callosum is most often recognized by identification of the accompanying somatic or facial anomalies. The slightly older infant may also be identified by accompanying anomalies or during the evaluation of seizures. Both neonates and infants may have feeding difficulties and swallowing apraxia (53). In children the usual clinical presentation is developmental delay, difficulty in school, or seizures, and the agenesis of the corpus callosum is identified incidentally as a result of the neuroimaging studies performed as part of the evaluation. Although the functional deficits accompanying agenesis of the corpus callosum are not progressive, it is not uncommon for a child to do well in school for a few years and then begin to fail when the work becomes harder, more abstract, and more complex.
Agenesis of the corpus callosum is also seen as a feature of many chromosomal and genetic mental retardation syndromes, as well as several hereditary metabolic diseases where the clinical presentation is dominated by the primary disease (64). Studies have demonstrated that individuals with corpus callosal agenesis perform significantly below unaffected individuals with respect to short and long delayed free recall and cued recall; additionally, they perform less well in original learning (27). From a functional standpoint, focal cortical dysplasias such as zones of disorganized lamination occur and may be epileptogenic (64). When the callosal defect is only part of a more pervasive disorder, the clinical picture is usually dominated by the primary condition. In correlation with the varied physical manifestations of this condition, neuropsychological efforts to characterize patients with agenesis of the corpus callosum have described atypical facial scanning with diminished attention to the eyes; as such, patients may exhibit impaired recognition of emotions in others (15). There may also be a measurable difference in sensory processing whereby sensory information, in particular auditory information, must be presented more slowly or with increased intensity in order to ensure adequate processing (25).
However, when agenesis of the corpus callosum is not associated with any other recognizable malformations, the defect may not be discovered except by serendipity when an MRI or CT scan is performed for headache or some other apparently unrelated symptom; the incidental discovery of corpus callosal agenesis has even been reported in a case of Parkinson disease (36). Such patients in whom agenesis of the corpus callosum may be identified coincidentally are thus classified as having isolated, or primary, agenesis of the corpus callosum; although intelligence may be normal, subtle neurologic, social, and learning deficits may still occur (58; 73). In studying MRI scans of in utero fetal brains, Knezovic and colleagues observed that callosal agenesis interferes with normal hippocampal formation and growth, resulting in underdevelopment that could potentially give rise to certain learning and memory deficits later in life (39).
Although agenesis of the corpus callosum would be expected to give rise to reduced interhemispheric transfer of sensory-motor information, reduced cognitive processing speed, and possibly deficits in complex reasoning, the finding of normal or nearly normal intelligence in in such patients suggest that other compensatory mechanisms have occurred (16). These patients may have developed extra-callosal communication pathways between hemispheres that allow them to function without evidencing a split-brain syndrome. Reorganization of the visual cortex and pathways in patients with callosal agenesis has also been demonstrated (13). One study reported no relationship between intelligence quotient and autism in corpus callosal agenesis, and there was no evidence that the presence of any residual corpus callosum differentiated those who manifested autism spectrum symptoms from those who did not (60). However, more recent studies have focused on the implication of corpus callosal agenesis on emotions and behavioral alterations seen in autism (04; 42; 75), as the corpus callosum is necessary for more complex processes involving emotions in a context of social interactions. Furthermore, the reduction in axonal connections between cortical areas would be expected to give rise to behavioral alterations in cases of autism.
The majority of individuals with anomalies of the corpus callosum are impaired with respect to cognitive function, which is more dependent on the degree of developmental disturbance in the brain in general than on the callosal defect itself. Nevertheless, the cognitive impairment is the chief factor that determines the prognosis in these patients. Infants with callosal defects should be monitored closely for developmental delay and may require early intervention as well as various other therapeutic interventions, such as occupational therapy, physical therapy, and speech therapy. Older children and school-aged children should probably undergo neuropsychologic testing in anticipation of possible school problems.
One study demonstrated that if agenesis of the corpus callosum with ventriculomegaly is associated with other malformations, a poor outcome is highly likely. Although the outcome of isolated callosal agenesis with fetal ventriculomegaly was generally better, more than 50% of affected patients had mild to moderate neurodevelopmental disabilities (54).
The failure of development of the corpus callosum results from a disturbance of the normal involution of the lamina terminalis. A variety of factors can disrupt normal embryonic events, giving rise to agenesis of the corpus callosum. These include chromosomal anomalies, single gene mutations, abnormal alteration of cell growth and proliferation (the neurocutaneous syndromes), and teratogenic exposures (fetal alcohol exposure, hyperglycinemia, fetal x-ray exposure, and other metabolic disturbances). A catalogue of the genes associated with agenesis of the corpus callosum has been developed (55).
In consideration of pathogenesis, timing is crucial in characterizing corpus callosal abnormalities and should always be considered when evaluating cases by imaging techniques or by neuropathologic examination at autopsy. With respect to the corpus callosum, the first axons originating from the lamina terminalis cross the midline in the callosal plate at 10 weeks gestation; at this point, axons of the anterior commissure had already crossed 3 weeks earlier at 7 weeks gestation. As such, a careful examination of both the anterior commissure and corpus callosum would permit more accurate timing of the insult; absence of both the anterior commissure and corpus callosum indicates that the malformative event occurred prior to 7 weeks of gestation; a preserved anterior commissure and an absent corpus callosum indicate that the insult occurred between 7 and 10 weeks of gestation (66), thus facilitating further correlation as to whether the observed abnormalities resulted from genetic versus acquired factors.
The mechanism by which inborn errors of metabolism such as hyperglycinemia or other embryotoxins lead to altered function of the lamina terminalis is not clear. In radiation-induced agenesis in mice, the defect results from 3 components: (1) death of callosal neurons in layer 3, (2) postnatal axonal elimination, and (3) absence of the glial sling necessary to guide the callosal axons (01).
Agenesis of the corpus callosum is seen in many chromosomal abnormalities, including trisomy 13, 18, 11q, 8 mosaic and partial, 8p11 to 23.1 translocation, 6 and mosaic, partial trisomy 8p, 21, 4p;t(4; 15), ring chromosome, various deletions and translocations, Kleinfelter syndrome (XXY), and Turner syndrome mosaicism (38; 61). It is also seen in metabolic conditions such as hyperglycinemia, fetal alcohol syndrome, Hurler syndrome, Leigh syndrome, Zellweger syndrome, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, histidinemia, lactic acidosis, Smith-Lemli-Opitz syndrome (cholesterol metabolism defect), and defects of very long-chain fatty acid metabolism (08; 40). Mutations in single genes may also be responsible for agenesis of the corpus callosum, some of which have also been observed in association with other clinical manifestations and syndrome (55). A defect in cytochrome C synthetase and K-Cl cotransporter KCC3 have been associated with agenesis of the corpus callosum (29). A contiguous gene syndrome localizing to Xp21, a condition with agenesis of the callosum and peripheral neuropathy localizing to chromosome 15q and other unlocalized familial conditions inherited in autosomal recessive, dominant, and X-linked patterns are known (18; 56; 30). Mutations in the TUBA1A (alpha-tubulin) gene associated with lissencephaly also sometimes results in agenesis of the corpus callosum (41; 06). Molecular alterations recently associated with corpus callosal agenesis, often accompanied by concomitant findings, include MKS1 mutation (05), loss of AMPD2 (48), EARS2 mutation (22), and PRICKLE1 mutation (11). Darki and colleagues found that 5 polymorphisms in the regulatory region of the ROBO1 gene were associated with white matter density in the posterior part of the corpus callosum pathways; 1 of these polymorphisms, specifically rs7631357, was also associated with the probability of connections to the parietal cortical regions, thus shedding further light onto the complexity of information transfer between the 2 hemispheres that may be compromised in abnormalities affecting the corpus callosum (23). Deletion of the ZEB1 gene has been found in corpus callosal agenesis associated with posterior polymorphous corneal dystrophy (19), and microdeletion of 1q44 has been implicated in a case with associated seizure and microcephaly (76). Other genetic mutations have also been reported in association with agenesis of the corpus callosum, including those involving DNA mismatch repair proteins PMS2 and DICER1 (20), DCC (47), and EGP5 (46). Patients with agenesis of the corpus callosum may have enlarged subcallosal interhemispheric fiber tracts such as the anterior commissure and the hippocampal commissure. Data demonstrate that some of the axons diverted by the absence of the corpus callosum can be found in the internal capsule where they travel in conjunction with the corticospinal tract to the spinal cord, where they are found in the ventral corticospinal tract (65). These pathways and the preservation of redundant pathways that would normally be eliminated during maturation probably account for the ability of these patients to transmit sensory and motor information between the hemispheres without the corpus callosum and the bilateral sensory and motor representation of the cortex (43; 31; 33).
Partial agenesis of the corpus callosum may also be the result of a disturbance of the lamina terminalis, in which case it usually is also accompanied by the formation of Probst bundles. The callosum begins rostrally and finishes at the splenium caudally. Thus, deficiency of the splenium is the most common developmental failure, followed by the rostrum, and least commonly the midbody of the corpus callosum (45). Alternatively, partial absence may represent secondary destruction of part of the callosum, in which case no Probst bundle is seen. The presence of the bundle of Probst, which can easily be demonstrated on most MRI studies in the dorsomedial wall of the hemispheres, helps to distinguish primary malformations from secondary (encephaloclastic) phenomena (44) and from the absence of the corpus callosum resulting from major malformation of the embryonic anlage of the corpus callosum. However, there are circumstances when the callosal axons join the ipsilateral internal capsule and descend with the corticospinal tract through the basis pontis and medullary pyramids to form an enlarged ventral corticospinal tract in the spinal cord; such rare instances demonstrate an alternate pathways for hemispheric callosal axons to cross, independent of the integrity of the corpus callosum (65).
Hypoplasia of the corpus callosum, which is defined as a completely formed corpus callosum less than 2 standard deviations below the normal size for age, represents a deficient number of callosal fibers (Bodensteiner et al 1990; 64).
In a study of a large population database, the combined prevalence of agenesis and hypoplasia of the corpus callosum was 1.8 per 10,000 live births (28). There was an increased risk with increasing maternal age and premature birth. Children with chromosomal anomalies had a 17.3% risk of callosal defects, and children with CNS anomalies had a 49.5% risk of developmental anomalies of the corpus callosum. In a consecutive series of 445 pediatric MRI scans, 14 (3.1%) were found to have anomalies of the corpus callosum, 5 with complete agenesis, 2 with partial agenesis, and 7 with hypoplasia of the corpus callosum (14). This does not reflect the incidence in the general population, as these scans were all performed for clinical indications of various types. In a study of 63 patients with complete (30) and partial (33) agenesis of the corpus callosum, 9 of the patients were able to function in the normal range (12).
Although no specific preventive measure is known, general nutritional status and prenatal vitamin (folate) and mineral (zinc) supplementation have been shown to decrease the incidence of some developmental anomalies (induction and midline clefts, respectively). Maternal age is known to be a risk factor for the chromosomal trisomies that are associated with a high incidence of agenesis of the corpus callosum.
Agenesis and partial agenesis of the corpus callosum have been described as features of many conditions, which share the expression of a detrimental event during early gestation (6 weeks to 5 months), whether secondary to a single gene defect chromosomal anomaly or metabolic disturbance (08; 40). Before the term "idiopathic agenesis of the callosum" is applied, the patient should be examined for somatic and facial anomalies, and laboratory screening tests should be done for the major metabolic abnormalities and chromosomal defects associated with this finding.
Hypoplasia of the callosum is somewhat different in that it is merely a marker of disturbed development elsewhere in the brain, resulting in deficient neuronal fibers crossing in the callosum. Mechanical forces, like those produced by hydrocephalus and extensive areas of tissue destruction later in life, can also result in thinning of the callosum. Interhemispheric lipomas, arachnoidal cysts, or neuroepithelial cysts may accompany partial callosal agenesis (10; 51).
Agenesis of the corpus callosum can be diagnosed by cranial ultrasonography in the fetus and infant, as well as by pneumoencephalography, CT scan, or MRI scan (54). Prenatal diagnosis of this condition has increased due to an increase in prenatal ultrasound studies, and numerous researchers have characterized ultrasonic fetal findings that are characteristic or highly predictive of this condition (62). The hippocampal commissure, the residual interhemispheric connection that is normally hidden by the formed corpus callosum itself, may be visualized in prenatal ultrasounds of approximately two-thirds of fetuses with complete agenesis (21). Wiechec and colleagues described 4 steps in the diagnosis of complete agenesis of the corpus callosum in fetal ultrasounds based on axial view findings of the brain, classifying ultrasonic parameters into 4 grouped patterns: A – normal third ventricular size with normal lateral ventricular size or mild ventriculomegaly; B1 – dilated third ventricle with normal lateral ventricle size; B2 – dilated third ventricle size with mild to moderate ventriculomegaly; C – dilated third ventricle with severe ventriculomegaly (77). Karl and colleagues introduced the cavum septi pellucidi (CSP) ratio as a marker for partial agenesis of the fetal corpus callosum. This is the ration of the length of the CSP relative to its width, as determined sonographically. Fetuses with partial agenesis of the corpus callosum typically demonstrated CSPs with shorter length, wider width, with an overall smaller length to width ratio (34).
In the postnatal period, the examination of choice is the MRI scan. The chief imaging features include wide separation of the lateral ventricles with loss of the normal convexity towards the midline and the high-riding third ventricle that is seen between the lateral ventricles. In most cases the Probst bundle can be seen as a bilateral mass of tissue interposed between the bodies of the lateral ventricles just above the level of the third ventricle. Radiographically, the presence of Probst bundle confirms that the absence of the callosum is a primary defect of embryonic development and not secondary to an earlier malformative event of midline patterning, such as holoprosencephaly, or to a later developmental abnormality (58).
Partial agenesis of the corpus callosum often cannot be appreciated except on the sagittal images of the MRI where the callosum can be clearly seen to be incomplete. "Hypoplasia of the corpus callosum" describes a completely formed callosum that is more than 2 standard deviations below the mean callosal area for age. As such, it should only be diagnosed after comparison of the relative sizes of the callosum to the size of the brain by quantitative image analysis because visual inspection alone is likely to result in underestimation of the relative size of the structure (14).
In a retrospective analysis, MRI features in a group of 201 patients with callosal agenesis were reviewed and compared (52). Among this patient population, 80% showed hypoplasia or dysplasia of the corpus callosum. Complete agenesis with other brain abnormalities was observed in 20% of cases, whereas complete agenesis alone was seen in 9%. White matter abnormalities were more frequently encountered in hypoplasia or dysplasia (28.2%) than in cases of complete agenesis (9.8%).
PET scanning may disclose local cortical hypometabolism that corresponds to an area of focal cortical dysplasia resulting in an epileptic focus, or on occasion an entire hemisphere may show altered metabolism; these findings may be useful in considering a surgical approach to the treatment of intractable seizures (35).
In the differential diagnosis and diagnostic work-up, it should be noted that abnormalities of the corpus callosum reflect a broad and diverse spectrum of morphologic variants, resulting from a wide range etiologic and pathogenetic factors. In many instances, the underlying cause remains undetermined despite thorough evaluations (52; 02; 37). Kidron and colleagues performed an autopsy study looking at 50 fetal autopsies with callosal defects (37). Four distinct groups of callosal abnormalities were categorized by morphologic, gross, and histologic examination of the corpus callosum, and the groups included complete, partial, hypoplastic, and mixed defects. It was noted that hypoplastic and mixed defects were associated with more abnormalities of the cerebral hemispheres and internal organs; cases of isolated corpus callosal agenesis comprised only 10% of the cases in this series, which was less than expected based on prenatal imaging.
There is no specific therapy for individuals with agenesis of the callosum. The comprehensive management of these patients requires attention to motor, social, and cognitive deficits. The physician should be alert to the possibility of visual problems, and growth should be monitored over the long term. Conditions that may be present in children with agenesis of the corpus callosum, particularly metabolic defects and seizures, may require specific therapy.
With additional experience and refinement of radiographic techniques, agenesis of the corpus callosum can now generally be confidently made, or at least highly suspected, on fetal sonography, especially when interpreted in conjunction with MRI (63; 72). As the antenatal diagnosis of agenesis of the corpus callosum has a significant effect on prognosis for the child, genetic counseling is warranted (57).
More severely handicapped individuals may have unusual physiological responses to ordinary doses of medications used in anesthesia. No predictive tests are available, and caution is the only safeguard.
Brian H Le MD
Dr. Le of Novant Health System has no relevant financial relationships to disclose.See Profile
Harvey B Sarnat MD FRCPC MS
Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.See Profile
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