Published online May 1, 2006
PEDIATRICS Vol. 117 No. 5 May 2006, pp. e928-e931 (doi:10.1542/peds.2005-1788)
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Third Ventricle Enlargement Among Newborn Infants With Trisomy 21

Michael S. Schimmel, MDa,b, Cathy Hammerman, MDa,b, Ruben Bromiker, MDa,b and Itai Berger, MDc

a Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel
b Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
c Neuropediatric Unit, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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OBJECTIVE. Our goal was to determine whether the third ventricle is significantly enlarged among neonates with trisomy 21, compared with infants without clinical signs of trisomy 21. This enlargement might be related to hypoplasia of the structures surrounding the third ventricle. These structures participate in cognitive development, and hypoplasia in this area may be responsible for some of the unique cognitive abnormalities observed among children with trisomy 21.

METHODS. Measurements of routine head sonographic scans of 57 term infants with trisomy 21 who were born between January 2000 and August 2005 were performed within 7 days after birth and were compared with measurements of head sonographic scans of 21 randomly selected, healthy, term infants without trisomy 21.

RESULTS. Although the 2 groups were of similar gestational ages, infants with trisomy 21 were generally smaller, with smaller head circumferences. Despite the smaller overall head circumference, both the width and length of the third ventricle were enlarged among the infants with trisomy 21. Vertical measurements of the lateral ventricles were similar for the 2 groups.

CONCLUSIONS. The third ventricle is an important diencephalic space. In our neonatal population, we did show significant enlargement of both the length and width of the third ventricle among the infants with trisomy 21, compared with the control group of unaffected newborns. We suspect that the unique neuropsychological development and cognitive dysfunction associated with trisomy 21 and the enlargement of the third ventricle in the neonatal period might be related.

Key Words: trisomy 21 • third ventricle • neurodevelopment • Down syndrome

Abnormal findings on neonatal head ultrasound scans can serve as predictors of abnormal neurodevelopmental outcomes. In this context, "abnormal findings" usually refer to major anatomic or clear pathological findings, such as hydrocephalus, agenesis of the corpus callosum, lissencephaly, or stroke. These findings are known to be potentially associated with neuropathological conditions. We would like to focus on measurements of the third ventricle, a structure that is usually tiny and thus rarely measured in the newborn population. The third ventricle is a diencephalic structure surrounded by the thalamus, hypothalamus, and deep white matter. To date, the third ventricle has not been associated directly with clear-cut, isolated, pathological conditions in the neonatal period (without hydrocephalus). This is in contrast to adults, for whom it has long been known that pathological conditions in the region of the third ventricle can result in cognitive changes.1,2

Trisomy 21 is the most common genetic cause of delayed mental development among human subjects.3 Pennington et al4 stated that "the brain of trisomy 21 babies appears normal at birth and is invariably abnormal by adulthood."4 However, other studies described anatomic brain abnormalities among children with trisomy 21 that can be seen earlier.5,6 These abnormalities include alterations of cortical lamination, reduced dendritic ramifications, and diminished synaptic formation,5 causing brain growth retardation that occurs after mid-infancy.6 This pattern of brain growth retardation is considered unique to children with trisomy 21, whether secondary to prenatal retardation of neurogenesis alone, which begins after gestational age of 22 weeks, as concluded by Schmidt-Sidor et al,6 or in combination with the postnatal abnormalities in synaptogenesis described by Becker et al.5 Whether the anatomic abnormalities manifest as early as the prenatal period, in mid-infancy, or only in adult life, none of those studies mentioned abnormalities in measurements of the third ventricle.

Subsequent neuropathological changes in the trisomy 21 population include features of early Alzheimer disease, which are seen by the age of 35 among many adults with trisomy 21.4 Even among children and young adults with trisomy 21 for whom Alzheimer disease has not yet developed, the neuropsychological profiles demonstrate a unique pattern of abnormalities.4,7 The typical language profile for people with trisomy 21 consists of poor production with greater compromise of morphosyntax than of lexical abilities, with relatively preserved comprehension.4,7

We hypothesized that the third ventricle would be enlarged among neonates with trisomy 21, compared with neonates without trisomy 21, as measured with head ultrasound scans shortly after birth. We also speculated that such enlargement might help explain some of the unique abnormalities in neurocognition of children with trisomy 21. Our hypothesis was based on the fact that structures surrounding the third ventricle participate in the normal neurodevelopment and are responsible for the affected cognitive skills.8–10


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
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This was a retrospective review of data collected for clinical purposes. Measurements of routine head sonographic scans of term infants with trisomy 21 who were born between January 2000 and August 2005 were performed within 7 days after birth and were compared with measurements of head sonographic scans of randomly selected, healthy, term infants without trisomy 21. The study of the term infants without trisomy 21 was approved by the human research committee of the Shaare Zedek Medical Center. Studies were performed with a HP ImagePoint, multispecialty, 7.5-mHz, curvilinear probe (Hewlett-Packard, Andover, MA). The studies were performed through the anterior fontanel at the level of the foramen of Monro, with a coronal view (Fig 1). The length and width of the third ventricle were measured twice for each patient; the largest measurements were used for calculations. Lateral ventricle size (vertical measurement) was evaluated anterior to the foramen of Monro notch. All measurements were performed by one physician (M.S.S.). Statistical significance was calculated with the t test and was defined as P < .05.


Figure 1
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  		FIGURE 1 Head ultrasound scans (coronal sections) for an infant with trisomy 21 (left) and a comparison subject (right).

 

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DISCUSSION
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Seventy-eight infants were evaluated, including 57 infants with trisomy 21 and 21 infants with no clinical suspicion of trisomy 21. Although the 2 groups were of similar gestational ages (39 ± 1 weeks vs 39 ± 1 weeks), infants with trisomy 21 were smaller (3.023 ± 0.355 kg vs 3.375 ± 0.399 kg; P = .001), with smaller head circumferences (32.9 ± 1.2 cm vs 34.9 ± 1.7 cm; P = .001). Despite the smaller overall head circumference (Table 1), both the width and length of the third ventricle were increased among the infants with trisomy 21. Vertical measurements of the lateral ventricle, taken for comparison, were similar for the 2 groups (Table 1).


View this table:
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  		TABLE 1 Lateral Ventricle and Third Ventricle Measurements

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study demonstrates that newborns with trisomy 21 have significantly enlarged third ventricles, compared with age-matched healthy neonates. To the best of our knowledge, this finding has not been described previously for this population. We suspect that the enlarged third ventricle might reflect abnormal intrauterine development of the surrounding structures.

Cognitive and neuropsychological profiles in trisomy 21 have identified global delays, with disproportionately impaired speech and language and major deficits in long-term and short-term verbal memory.4,7 Compared with these dramatic impairments, visuospatial processing skills are relatively preserved.11,12 Trisomy 21-specific neuropsychological and cognitive dysfunctions have been correlated with hippocampal, prefrontal, and cerebellar functions.3,4,7 Even in those studies, however, it was admitted that this is not the only source of abnormal development among children with trisomy 21. Therefore, there seem to be other abnormalities, not involving the prefrontal cortex, cerebellum, or hippocampus, that contribute to the unique cognitive profile of children with trisomy 21. The dimensions of the third ventricle might explain some of these other abnormalities. We speculate that the third ventricle enlargement we observed probably reflects hypoplasia of one or more of the surrounding structures. These structures include the thalamus, hypothalamus, and deep white matter, which participate in the normal cognitive processes of attention, verbal performance, and visuospatial memory.8–10

Although it is possible that enlargement of the third ventricle reflects loss of mass in more-distant brain structures, we would expect this to lead to enlargement of the lateral ventricles as well, which we did not observe. Until recently, understanding of the structural brain abnormalities among infants with trisomy 21 was based almost exclusively on autopsy studies. Only lately have technical improvements in imaging allowed more-extensive in vivo exploration. Pinter et al3 studied children and adults (5–23 years of age) with trisomy 21 with high-resolution MRI and demonstrated "abnormal volumes of specific regional tissue components," ie, smaller cerebellar volume, smaller volumes of cerebral gray and white matter, and larger adjusted volumes of subcortical and parietal gray matter and temporal white matter components. The authors noted that "these abnormalities from an early age suggest that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive deficits in trisomy 21."3

Although MRI volumetric studies of adults with trisomy 21 showed volumes of basal ganglia and other diencephalic structures to be within the normal range, none of those previous studies examined these structures in the brains of neonates with trisomy 21. In our neonatal population, the sizes of the lateral ventricles were similar in the 2 groups but both the width and length of the third ventricle were increased significantly among neonates with trisomy 21.

The association between third ventricle enlargement and cognition has been described for other populations but not trisomy 21. Among adults, several cognitive variables (attention, verbal performance, and visuospatial memory), similar to those that have been observed to be impaired with trisomy 21, are predicted by third ventricle width.2 Third ventricle enlargement has been described for a broad spectrum of brain disorders, such as multiple sclerosis,1 schizophrenia,13 first-episode psychosis,14 anterograde amnesia,15 and severe head injury.16 Several authors even concluded that the diameter of the third ventricle can serve as a reliable cognitive prognostic tool.2,17

Enlargement of the third ventricle among adults, in relation to the whole-brain volume, is associated with deficient abstraction/flexibility, language, and attention/concentration.18 Berg et al,17 in their study of multiple sclerosis, found an association between the diameter of the third ventricle (determined with transcranial ultrasonography) and neuropsychological disability assessments. Benedict et al,2 in a different study assessing neuropsychological impairment in multiple sclerosis, concluded that "all cognitive variables were predicted by third ventricle width." Unlike other measurements of brain atrophy, enlargement of the third ventricle is considered more sensitive and more specific; because it can be detected early, it is a good prognostic tool.2

We hypothesized that the third ventricle would be enlarged among neonates with trisomy 21, compared with neonates without trisomy 21, as measured with head ultrasonography shortly after birth. We also speculated that such enlargement might help explain some of the unique abnormalities in neurocognition among children with trisomy 21.

Additional studies are needed to correlate the specific cognitive developmental level and the size of the third ventricle among children with trisomy 21. If such a relationship can be confirmed, then it may pave the way for future studies aimed at assessing the size of the third ventricle as a predictive neurodevelopment tool in trisomy 21. We speculate that volumetric MRI studies can help answer some of the questions raised here.


   FOOTNOTES
 
Accepted Oct 24, 2005.

Address correspondence to Michael S. Schimmel, MD, Department of Neonatology, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel. E-mail: schimmel{at}szmc.org.il

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Bakshi R, Benedict RH, Bermel RA, et al. T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study. Arch Neurol. 2002;59 :62 –68[Abstract/Free Full Text]
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  6. Schmidt-Sidor B, Wisniewski KE, Shepard TH, Sersen EA. Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months. Clin Neuropathol. 1990;9 :181 –190[ISI][Medline]
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  15. Aggleton JP, McMackin D, Carpenter K, et al. Differential cognitive effects of colloid cysts in the third ventricle that spare or compromise the fornix. Brain. 2000;123 :800 –815[Abstract/Free Full Text]
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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