Holoprosencephaly Neuroimaging
HOLOPROSENCEPHALY (HPE) is characterized by failure of cleavage of the embryonic
prosencephalon, an event which is normally complete by embryonic day 35 and
results in both differentiation into diencephalon and telencephalon, as well as
separation of the telencephalon into two cerebral hemispheres. HPE is generally
classified as either middle interhemispheric variant (MIH), lobar, semi lobar, or alobar. These are not absolute
distinctions and do not necessarily correlate with clinical status or genotype.
As a rule, however, those with alobar HPE are most severely affected, and those
with MIH and lobar HPE are least affected. In reality, HPE is a continuum of forebrain
malformations and is sometimes accompanied by other associated cortical
malformations.
MIDDLE INTERHEMISPHERIC VARIANT (MIH) has neuroimaging features that are different from classic HPE. Unlike classic HPE where the most severely nonseparated region of the hemispheres is the basal forebrain, in MIH the posterior frontal and parietal lobes are affected. The anterior portions of the frontal lobes and the occipital lobes are well separated in MIH. The genu and splenium of the corpus callosum appear normally formed, but the callosal body is absent. The hypothalamus and lentiform nuclei appear normally separated, but the caudate nuclei and thalami are incompletely separated in many cases. Usually, he sylvian fissures are oriented nearly vertically and are abnormally connected across the midline over the vertex of the brain. Approximately two thirds of MIH patients have either subcortical heterotopic gray matter or cortical dysplasia.
LOBAR HPE is the least severe of the major types of HPE. The cerebral hemispheres
are reasonably well separated and there is some frontal horn development noted in
the lateral ventricles. The ventricles still appear dysmorphic due to absence of
the septum pellucidum. Often the posterior half of the corpus callosum is formed.
The third ventricle is usually well formed as well. Varying degrees of basal
ganglia and thalamic fusion may be seen, as may a dorsal cyst. Midline
craniofacial defects are often absent or mild, sometimes restricted to
hypotelorism, but may include cleft lip and palate, as well as other
abnormalities.
SEMILOBAR HPE is characterized by less development of anterior brain structures. The splenium of the corpus callosum is present but more anterior portions are usually absent. Separation of the hemispheres is often noted posteriorly with presence of a falx cerebri and interhemispheric fissure in this region. A small, partially formed third ventricle is often noted. More significant fusion of anterior brain structures (cortex, basal ganglia, thalamus) is noted compared to the lobar variant. A dorsal cyst may be seen. In mild cases, lack of frontal horn development distinguishes this from the lobar type. Midline craniofacial defects such as cleft lip and palate may be present but, as with lobar HPE, in many cases only subtle facial abnormalities are noted.
ALOBAR HPE is the most severe type. No significant separation into hemispheres is noted. In general, there is agenesis of the corpus callosum, the third ventricle is absent, and thalami and basal ganglia are fused. The ventricular system usually has the appearance of a monoventricle (or holoventricle). A dorsal cyst, which often communicates with the monoventricle, is frequently noted. Clinically, these patients are often noted to have more significant midline craniofacial defects, including cases of cyclopia.
OFTEN, hydrocephalus is initially severe in children with HPE and the only MRI is done prior to shunt placement. Caution should be exercised in diagnosing HPE at this point, as one may misinterpret lobar and semi lobar variants for alobar due to brain compression. It is important to repeat the MRI post-shunt when it is possible to determine which brain structures are affected. It is usually quite difficult to evaluate midline structures on CT scans alone.
An example of the difficulty of characterizing HPE based on a pre-shunt scan is demonstrated here. Note that the brain appears on sagittal view like a typical alobar variant, due to the large dorsal cyst and apparent lack of posterior cortical development. Thalami are fused. Post-shunt CT shows fair development of the posterior cortices, communication of the dorsal cyst with the third ventricle, and now more easily seen development of the anterior horns, thus leading to the correct diagnosis of lobar HPE. In this case, a repeat MRI would be valuable to reassess midline anatomy.
NEUROIMAGING EVALUATION of HPE is best accomplished by MRI. In all suspected cases the scan should include axial, sagittal and coronal sequences to enable complete evaluation of midline structures. Also, thin sections are recommended; ideally no greater than 3 mm thick, with spacing of 0.5 mm. Even better are volumetric protocols, which generally have 1.5 mm slice thickness with no gaps.
Until now, a lack of standardization of protocols has made it difficult to meaningfully classify this disorder. The individuals to the right have been instrumental in helping the Carter Centers to develop standardized MRI sequences to obtain 3-dimensional structural data for HPE, which can then be compared across many institutions. It is hoped that utilization of improving technology to fully characterize brain structure in HPE will lead to better classification schemes, important genotype-phenotype correlations, and ultimately to a better understanding of etiologies.
References
Simon EM, Hevner R, Pinter JD, Delgado M, Clegg N, Kinsman S, Hahn JS, Barkovich AJ. Assessment of the deep gray nuclei in holoprosencephaly. AJNR American Journal of Neuroradiology. 2000, 21:1955-1961. PMID: 11110554
Simon EM, Hevner R, Pinter JD, Clegg NJ, Delgado M, Kinsman S, Hahn JS, Barkovich AJ. The dorsal cyst in holoprosencephaly and the role of the thalami in its formation. Neuroradiology, 2001, 43:787-791. PMID: 11594433
Simon ER & Barkovich AJ. Holoprosencephaly: new concepts. Magn Reson Imaging Clin N Am 2001, 9:149-64. PMID 11278187
Simon EM, Hevner R, Pinter JD, Clegg NJ, Delgado M, Kinsman SL, Hahn JS, Barkovich AJ. The middle interhemispheric variant of holoprosencephaly. AJNR American Journal of Neuroradiology, 2002, 23:151-155. PMID: 11827888
Barkovich AJ , Simon EM, Clegg NJ, Kinsman SL, Hahn JS. Analysis of the cerebral cortex in holoprosencephaly with attention to the Sylvian Fissure. AJNR American Journal of Neuroradiology, 2002, 23:143-150. PMID: 11827887
