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DOI: 10.1148/radiol.2401050674
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(Radiology 2006;240:194-202.)
© RSNA, 2006

Pediatric Imaging

Limbic Tract Anomalies in Pediatric Myelomeningocele and Chiari II Malformation: Anatomic Correlations with Memory and Learning—Initial Investigation1

Behroze Vachha, MBBS, PhD, Richard C. Adams, MD and Nancy K. Rollins, MD

1 From Pediatric Developmental Disabilities, Texas Scottish Rite Hospital for Children, Dallas, Tex (B.V., R.C.A.); Departments of Pediatrics (B.V., R.C.A.) and Radiology (N.K.R.), University of Texas Southwestern Medical Center, Dallas, Tex; and Department of Radiology, Children's Medical Center of Dallas, 1935 Motor St, Dallas, TX 75235 (N.K.R.). Received April 22, 2005; revision requested June 16; revision received June 28; accepted July 8; final version accepted September 2. Address correspondence to N.K.R. (e-mail: Nancy.rollins{at}childrens.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively determine anomalies of limbic tracts and to describe the relationship between these anomalies, seen on diffusion-tensor magnetic resonance (MR) and fiber tract (FT) reconstruction images, and learning and memory in children with myelomeningocele (MM) and Chiari II malformation.

Materials and Methods: The investigation was HIPAA compliant and approved by institutional review boards; informed consent was obtained. In seven male and six female patients (aged 6 months to 16 years) with MM and Chiari II malformation, diffusion-tensor imaging and FT reconstruction were performed. FT reconstruction was generated with fractional anisotropy continuous tracking algorithm and manually drawn regions of interest. Limbic tract abnormalities were assessed on FT reconstruction images by an experienced pediatric neuroradiologist blinded to results of cognitive testing. Nine patients met criteria for memory and learning testing by a trained cognitive neuroscientist blinded to MR results. Exact Wilcoxon rank sum test was used to compare performance with learning and memory tasks in two groups.

Results: Eleven of 13 patients had defects within fornices and/or cingulum; three patients had aberrant fibers of cingulum. In nine patients, six had deficits in general memory; four, in learning; and four, in both. Atresia or hypoplasia of crura and body of fornices was noted in six patients with memory deficits and four patients with learning deficits. Five of six patients with memory deficits and three of four with learning deficits had hypoplasia or atresia of cingulum. Exact Wilcoxon rank sum test demonstrated significantly poorer performance for nonverbal immediate recall tasks in patients with anomalies of the fornix compared with those without (P = .04, exact two-tailed test).

Conclusion: Diffusion-tensor and FT reconstruction images revealed that limbic fiber abnormalities were common in patients with MM and Chiari II malformation. Nonverbal immediate recall task performance appeared to be related to abnormalities of the fornix.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Diffusion-tensor imaging, a relatively new magnetic resonance (MR) technique, provides noninvasive visualization of white matter tracts in the human brain, which may not be visible with routine MR imaging. Diffusion-tensor data may be displayed as fractional anisotropic maps, on which brightness indicates diffusion anisotropy, or as two-dimensional color maps, on which image brightness indicates diffusion anisotropy, whereas the color indicates the tract orientation (1–3). Fiber tracking may be performed by defining a region of interest on the color maps or fractional anisotropic maps and interrogating the region of interest for fibers having a minimal fractional anisotropy that is set by the user (2–4). The resultant three-dimensional image shows axonal projections. Scattered reports on the use of diffusion-tensor imaging and fiber tract (FT) reconstruction in patients with some congenital brain malformations are available. These malformations include callosal agenesis, cortical dysplasia, lissencephaly, and holoprosencephaly (5–8). The application of these techniques in patients with Chiari II malformation has not been reported, to our knowledge.

Myelomeningocele (MM), a relatively common congenital disorder characterized by the protrusion of the spinal cord and its coverings through a defect in the bony vertebral column, is the leading cause of infantile paralysis in the world today (9). The defect usually is accompanied by Chiari II malformation (10). Patients with MM and Chiari II malformation often show differences in temperament, memory, and learning patterns despite average intelligence (11,12). The limbic system, in particular the hippocampal formation, fornix, and cingulate gyrus, is integral to declarative memory and learning (13). Abnormalities of the limbic structures may correlate with emotional, memory, and learning problems in children with MM and Chiari II malformation (14). Thus, the purpose of our study was to prospectively determine whether there are anomalies of the white matter tracts of the limbic system and to describe the relationship between detectable anomalies of the limbic tracts, as seen on diffusion-tensor images and FT reconstruction images, and formal measurements of learning and memory in children with MM and Chiari II malformation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Patients
Our prospective Health Insurance Portability and Accountability Act–compliant study was approved by the investigational review boards of all three institutions. Informed consent was obtained from legal guardians. A convenience sample of five male and eight female patients (age range, 6 months to 16 years) with MM and Chiari II malformation underwent diffusion-tensor imaging, and FT reconstruction was performed. Nine of 13 patients with Chiari II malformation who were recruited into the imaging arm of the study met eligibility criteria, which are listed later. These patients were referred for both investigation of limbic tract abnormalities and formal testing of learning and memory. The remaining four patients were recruited into the imaging arm of this study but did not meet eligibility criteria for cognitive testing: Two patients were younger than 5 years of age and two patients did not speak English.

Inclusion criteria for cognitive testing were as follows: (a) diagnosis and treatment of hydrocephalus before 12 months of age, (b) monolingual English-speaking background, and (c) well-controlled seizures with no change in anticonvulsant medication within the past 3 months. Criteria for exclusion from the study were as follows: (a) history of any previous shunt infection, (b) existing shunt malfunction or shunt malfunction within the previous 3 months, (c) uncorrected sensory (auditory or visual) acuity deficits or motor disabilities that would preclude a response with the pointing of a finger, (d) a prior diagnosis of mental retardation, (e) prior diagnosis of attention-deficit hyperactivity disorder, (f) recent diagnosis of clinical depression, and (g) age younger than 5 years. Although other patients with MM and Chiari II malformation underwent routine clinical MR imaging during the 11 months in which this study was conducted, diffusion-tensor imaging and FT reconstruction were not performed because the parents refused to participate or the patients were unable to cooperate for the diffusion-tensor acquisition.

Intelligence and Memory Testing
Determination of normal general intelligence scores (full-scale IQ test) was performed by using the Wechsler Intelligence Scale for Children (15) in eight of nine patients. The other patient was 5 years old and was the youngest child tested, and assessment was performed with the Wechsler Preschool and Primary Scale of Intelligence (16) in this child. Verbal and nonverbal memory skills were assessed by using the Children's Memory Scale (17). Memory standard scores were obtained within two main dimensions. These dimensions were (a) a general memory index, which reflected a global measurement of memory function that comprised the immediate and delayed recall of a word-pair list and a story (verbal task) and the immediate and delayed recall of faces and a spatial location of a dot pattern (nonverbal task), and (b) a learning index that was based on the patient's ability to process, learn, and recall a word-pair list (verbal task) and the spatial location of a dot pattern (nonverbal task) across three learning trials. Standard scores also were computed for the four components of the general memory index: verbal immediate recall, verbal delayed recall, nonverbal immediate recall, and nonverbal delayed recall (Table 1). Cognitive testing was performed by a trained cognitive neuroscientist with 5 years of experience (B.V.) who was blinded to the results of MR imaging.


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  		Table 1. Description of Memory and Learning Tasks Assessed

 
Imaging
Sagittal and transverse MR imaging was performed with a 1.5-T unit (Achieva Release 1.0; Philips Medical Systems, Best, the Netherlands), a T1-weighted spin-echo sequence (repetition time msec/echo time msec, 500/12; number of signals acquired, two), and a 4-mm section thickness. Sagittal, transverse, and/or coronal MR imaging was performed with a T2-weighted fast spin-echo sequence (3500–4500/90–100; number of signals acquired, two to three) and a 4–5-mm section thickness. In children 12 months of age and older, a transverse fluid-attenuated inversion-recovery sequence (repetition time msec/echo time msec/inversion time msec, 8000/120/230) was performed with a 4–5-mm section thickness. Diffusion-tensor MR imaging was performed with a six-channel sensitivity encoding head coil operating in the receive mode and applying high angular resolution diffusion imaging (2) isotropic diffusion-weighted gradients by using a single-shot spin-echo echo-planar sequence and a sensitivity encoding factor of 2.5 and an echo-planar imaging factor of 35. Other parameters were as follows: 7357/98; b value, 700 sec/mm2; matrix, 112 x 256; field of view, 246 x 246 mm; number of sections, 55; section thickness, 2.2 mm; no gap; and number of diffusion-weighting directions, 15. The diffusion-tensor imaging sequence was repeated three times with one signal acquired, for a total image acquisition time of 7 minutes. A T1-weighted fast field echo with an inversion prepulse sequence (15/4.7; flip angle, 20°) was performed by using the same image resolution as was used for diffusion-tensor imaging to facilitate anatomic correlation.

The raw data obtained from the diffusion-tensor sequences and the anatomic coregistration images were transferred to an off-line personal computer (Optiplex GX280; Dell, Round Rock, Tex) that was equipped with software (Philips Research Imaging Development Environment, version 4.1V3; Philips Medical Systems) for image registration and fiber tracking. The three diffusion-tensor imaging raw data sets were processed by using registration software (Diffusion Registration Tool, release 0.4; Phillips Medical Systems). Automated section-by-section registration was performed for each acquisition, and correction was performed for motion between sections and between acquisitions. The three corrected data sets were averaged together and saved as a new raw data file. Fiber tracking was generated by using the fractional anisotropy continuous tracking algorithm (4). Tracking was performed (N.K.R.) with manual placement of a 3–5-mm2 region of interest over the cingulum and fornices, as has been described by other investigators, or with the use of an automated three-dimensional region of interest (2,3). The three-dimensional region of interest was generated by a single click on a desired structure; a flood-fill voxel comparison algorithm was used to determine which adjacent voxels belonged to the three-dimensional region of interest. Tract propagation was terminated when the fractional anisotropy was 0.15 and the internal angle was 0.75°.

Image Analysis
The routine MR images and FT reconstruction images were assessed by a Certificate of Added Qualifications–certified pediatric neuroradiologist (N.K.R.) with 19 years of experience who was blinded to the results of cognitive testing. The pediatric neuroradiologist assessed routine MR images qualitatively with respect to the intactness of the corpus callosum. A corpus callosum that was completely formed and subjectively normal in thickness was described as normal, whereas a completely formed corpus callosum that was subjectively attenuated in thickness was deemed intact but thin. A corpus callosum that was foreshortened in an anteroposterior dimension or that was incompletely formed was described as one that had dysgenesis. The severity of the Chiari II malformation, in terms of the degree of hindbrain herniation and cerebellar and brainstem hypoplasia, was noted. The pediatric neuroradiologist noted whether a decompressive suboccipital craniectomy had been performed and also indicated the presence of other cerebral malformations, such as the absence of the septum pellucidum and the presence of cortical dysplasia. The hippocampal formations were assessed for size and morphologic features on the coronal T2-weighted MR images. The position of the ventricular shunt was noted to determine whether defects in the fornix were related to the shunt. The sizes of the lateral ventricles on the transverse images were noted; the ventricles were judged as small, moderately enlarged, or markedly enlarged. The continuity, symmetry, and subjective thickness of the columns of the fornix, crura of the fornix, body of the fornix, and the fimbria of the hippocampus, as seen by using fiber tracking, were noted. The cingulum was assessed for the presence of and subjective thickness of the preseptal, frontoparietal, and temporal segments, which are known to be present in the normal brain from birth (1,2).

Statistical Analysis
Among the patients studied, nine met eligibility criteria for neurocognitive assessment according to validated formal measurements outlined previously. To assess outcomes most conservatively, given the small sample size, the nonparametric exact Wilcoxon rank sum test (P = .05) was performed with statistical software (SAS/STAT, version 9.1.2, 2004, SAS System for Windows; SAS Institute, Cary, NC). Exact Wilcoxon rank sum tests were used to compare each of the continuous memory and learning indexes (nonverbal immediate recall, nonverbal delayed recall, verbal immediate recall, verbal delayed recall, general memory index, and learning index) according to two groups (normal fornix vs abnormal fornix), with a P value of .05 considered to indicate a significant difference. Similarly, performance differences between groups with a normal cingulum versus an abnormal cingulum on the basis of diffusion-tensor imaging findings were evaluated at a significance level of P = .05. For this pilot study, significance levels were not adjusted for multiple comparisons.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Conventional MR Imaging
At routine MR imaging, four patients had a corpus callosum that was of normal thickness and fully formed, three patients had an intact but thin corpus callosum, and six patients had dysgenesis of the corpus callosum. At routine imaging, no patients had total callosal agenesis. Eight patients had minimal hindbrain herniation associated with a subjectively normal brainstem caliber, two patients had moderate hindbrain herniation associated with hypoplasia of the brainstem and had undergone decompressive suboccipital craniectomy, and three patients had severe hindbrain herniation associated with marked brainstem hypoplasia; one patient had undergone decompressive suboccipital craniectomy.

Eleven patients had an indwelling ventriculoperitoneal shunt, which had been inserted through a right frontal approach in six patients. Three patients had an indwelling right posterior parietal shunt, and two patients had a left posterior parietal shunt. One patient had undergone endoscopic third ventriculostomy through a right frontal approach; the right frontal shunt had been removed. One patient had not undergone cerebrospinal fluid diversion, and the ventricles were moderately dilated. This patient had undergone prenatal closure of a lumbar MM at an estimated gestational age of 24 weeks.

Overall, the ventricles were well decompressed and symmetric in eight patients, were asymmetric and decompressed in two patients, and were dilated in the absence of clinical evidence of shunt malfunction in three patients. No patient had neuronal migration anomalies, although stenogyria was observed over the mesial surfaces of the parieto-occipital lobes in eight of 13 patients (10). One patient had agenesis of the septum pellucidum. Coronal T2-weighted MR images had been acquired in eight of nine patients who underwent cognitive testing; the size and morphologic features of the hippocampi were normal in four patients and abnormal in four patients (Table 2). In the other five patients, four of whom did not undergo cognitive testing, coronal T2-weighted MR images had not been acquired.


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  		Table 2. Anomalies of the Limbic Tracts and Cognitive Findings in MM- and Chiari II Malformation

 
FT Reconstruction
As seen on FT reconstruction images, the fornices were continuous, symmetric in size, and subjectively of normal thickness in four patients with MM and Chiari II malformation (Fig 1); intact but thin in one patient; and abnormal in eight patients. Four patients had defects in the crura and the body of the fornix, with preservation of the fimbria of the hippocampus and columns of the fornix (Fig 2), whereas four patients had thinning of the crura and the body of the fornices (Fig 3); the fimbria of the hippocampus and the columns of the fornix were consistently intact. There was no correlation between defects of the fornices and the position of the ventriculoperitoneal shunt. Normal hippocampi seen in four patients were associated with normal fornices as depicted with FT reconstruction in one patient and with abnormal fornices in three patients.


Figure 1
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  		Figure 1: Sagittal FT reconstruction image shows normal cingulum (thick arrows) and fornix (thin arrows) in 6-month-old boy with Chiari II malformation who was too young to undergo cognitive assessment. A = anterior, P = posterior.

 

Figure 2
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  		Figure 2: Transverse bottom-up FT reconstruction image of fornices (short arrows) and anterior commissure (long arrows) in 14-year-old boy with no memory or learning problems. Note the symmetric defects in the crura of the fornix (arrowheads). L = left, R = right.

 

Figure 3
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  		Figure 3a: Sagittal images show abnormal limbic fibers in 5-year-old girl with memory and learning deficits. (a) T1-weighted spin-echo MR image (400/12; two signals acquired) shows severe hindbrain deformity and dysmorphic corpus callosum. (b) FT reconstruction image shows incomplete atrophic cingulum (long arrows) and thin fornix (short arrows). A = anterior, P = posterior.

 

Figure 3
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  		Figure 3b: Sagittal images show abnormal limbic fibers in 5-year-old girl with memory and learning deficits. (a) T1-weighted spin-echo MR image (400/12; two signals acquired) shows severe hindbrain deformity and dysmorphic corpus callosum. (b) FT reconstruction image shows incomplete atrophic cingulum (long arrows) and thin fornix (short arrows). A = anterior, P = posterior.

 
The cingula were completely formed and subjectively of normal thickness in three patients. Three patients had absence of the preseptal portions of the cingulum, whereas the frontoparietal and temporal segments were normal. In seven patients, the frontoparietal or temporal segments of the cingulum were atretic or markedly hypoplastic (Figs 4 and 5), and in addition, preseptal portions of the cingulum were absent. A completely formed corpus callosum, seen in six patients, was associated with a normal cingulum in three patients, absence of the preseptal portion of the cingulum in two patients, and asymmetric defects in the cingulum in one patient. A corpus callosum with dysgenesis that was seen in six patients was consistently associated with an abnormal cingulum. In two of six patients with callosal dysgenesis, the preseptal segments of the cingulum were absent, whereas four patients with callosal dysgenesis also had hypoplasia or atresia of the frontoparietal or temporal segments of the cingulum.


Figure 4
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  		Figure 4: Sagittal FT reconstruction image in 14-year-old girl with general memory and learning impairment. Defect in right crus of the fornix (short straight arrows) and intact left fornix (curved arrow) are observed. Temporal segment of left cingulum (long straight arrow) is attenuated compared with the normal right temporal segment (arrowhead).

 

Figure 5
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  		Figure 5: Oblique sagittal FT reconstruction image in 5-year-old girl with Chiari II malformation complicated by agenesis of septum pellucidum. Cognitive testing was not performed. Fornices (long arrow) are caudally displaced and right cingulum (short arrow) is deficient, whereas left cingulum (arrowhead) is thin but intact. Rostral fibers of corpus callosum partially obscure cingulum. A = anterior, P = posterior.

 
The presence of aberrant fibers of the cingulum over the callosal body, which was seen in three patients, was associated with an abnormal corpus callosum in two patients (Figs 6, 7) and an intact but thin corpus callosum in one patient.


Figure 6
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  		Figure 6a: Images show aberrant fibers of cingulum in 7-year-old boy with no memory and learning deficits. The cingulum and fornices are otherwise intact. (a) Sagittal T2-weighted fast spin-echo MR image (3500/120, two signals acquired) shows corpus callosum with dysgenesis, shortened in anteroposterior dimension with absence of splenium. Posterior fossa shows stigmata of Chiari II malformation. (b) Sagittal color map shows that corpus callosum is composed of red callosal fibers (short arrow) and green fibers (long arrow) derived from the cingulum and that they cannot be differentiated from each other on routine MR images. (c) Transverse top-down FT reconstruction image shows fibers of the cingulum (arrow) crossing obliquely over corpus callosum and normally positioned frontoparietal segments of the cingulum (arrowheads).

 

Figure 6
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  		Figure 6b: Images show aberrant fibers of cingulum in 7-year-old boy with no memory and learning deficits. The cingulum and fornices are otherwise intact. (a) Sagittal T2-weighted fast spin-echo MR image (3500/120, two signals acquired) shows corpus callosum with dysgenesis, shortened in anteroposterior dimension with absence of splenium. Posterior fossa shows stigmata of Chiari II malformation. (b) Sagittal color map shows that corpus callosum is composed of red callosal fibers (short arrow) and green fibers (long arrow) derived from the cingulum and that they cannot be differentiated from each other on routine MR images. (c) Transverse top-down FT reconstruction image shows fibers of the cingulum (arrow) crossing obliquely over corpus callosum and normally positioned frontoparietal segments of the cingulum (arrowheads).

 

Figure 6
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  		Figure 6c: Images show aberrant fibers of cingulum in 7-year-old boy with no memory and learning deficits. The cingulum and fornices are otherwise intact. (a) Sagittal T2-weighted fast spin-echo MR image (3500/120, two signals acquired) shows corpus callosum with dysgenesis, shortened in anteroposterior dimension with absence of splenium. Posterior fossa shows stigmata of Chiari II malformation. (b) Sagittal color map shows that corpus callosum is composed of red callosal fibers (short arrow) and green fibers (long arrow) derived from the cingulum and that they cannot be differentiated from each other on routine MR images. (c) Transverse top-down FT reconstruction image shows fibers of the cingulum (arrow) crossing obliquely over corpus callosum and normally positioned frontoparietal segments of the cingulum (arrowheads).

 

Figure 7
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  		Figure 7a: Moderate ventricular enlargement without shunt and anomalous cingulum in 13-month-old girl who had undergone prenatal closure of lumbar MM at 24 weeks gestational age. (a) Sagittal T1-weighted spin-echo MR image (400/12, two signals acquired) shows corpus callosum with dysgenesis. (b) Transverse top-down FT reconstruction image shows multiple white matter bundles (arrows) oriented anteroposteriorly above body of corpus callosum. The corpus callosum with dysgenesis is composed of callosal fibers and aberrant cingulum, and they cannot be differentiated on routine MR images.

 

Figure 7
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  		Figure 7b: Moderate ventricular enlargement without shunt and anomalous cingulum in 13-month-old girl who had undergone prenatal closure of lumbar MM at 24 weeks gestational age. (a) Sagittal T1-weighted spin-echo MR image (400/12, two signals acquired) shows corpus callosum with dysgenesis. (b) Transverse top-down FT reconstruction image shows multiple white matter bundles (arrows) oriented anteroposteriorly above body of corpus callosum. The corpus callosum with dysgenesis is composed of callosal fibers and aberrant cingulum, and they cannot be differentiated on routine MR images.

 
Relationship between Limbic Tract Anomalies and Results of Fiber Tracking
Group mean global intelligence scores for the nine patients with MM and Chiari II malformation who underwent neurocognitive testing were in the average range (mean full-scale IQ, 95.3 ± 7.7 [standard deviation]; range, 84–106). With respect to the overall general memory index, performance in three of nine patients tested was average (standard score, ≥85); two of three patients with normal overall general memory scores had normal fornices, and one patient with average performance for overall general memory tasks had defects only within the crura of the fornix. Two of three patients with average memory performance had intact cingula, whereas one had crossing fibers of the cingulum. Six of nine patients had overall general memory deficits (standard score, <85). Six of six patients had varying degrees of deficits of the fornix; frank defects in the fornix were seen in five (83%) of six patients, whereas one patient with general memory deficits had intact fornices with thinning of the crura and the body of the fornix. Abnormalities of the cingulum were seen in four of six patients with general memory deficits.

With respect to the learning index, four of nine patients with MM and Chiari II malformation demonstrated below-average performance (standard score, <85). Varying degrees of abnormalities of the fornix were revealed in all four patients; three of four patients had frank defects in the fornices, and one patient had intact but thin fornices. Three of four patients with below-average learning indexes had an anomalous or a deficient cingulum; one of four patients had a normal cingulum but abnormal fornices. Performance for learning tasks was average in five of nine patients; three of five patients had an intact cingulum, whereas two of five patients had an anomalous or a deficient cingulum. Two of five patients with average performance for learning tasks had normal fornices; the remaining three had abnormal fornices.

With the nonparametric exact Wilcoxon rank sum test, statistically significant differences were demonstrated in performance between the group with a normal fornix and the group with an abnormal fornix only for the tasks involving nonverbal immediate recall (P = .04, two-tailed test). No significant differences were seen between a normal and an abnormal anatomic structure of the fornices and the performance with the general memory index, the learning index, and the other verbal and nonverbal memory tasks (P > .05). No significant differences were seen between a normal and an abnormal structure of the cingulum and the performance for learning and memory tasks (P > .05).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
As seen on diffusion-tensor MR images and FT reconstruction images, limbic fiber abnormalities were detected in our sample of patients with MM and Chiari II malformation. The limbic system is thought to be integral to primitive behavior and emotional response, as well as learning and memory (18), and is composed of inner and outer arches (19). The paraterminal gyrus, supracallosal gyrus, fasciolar gyrus, dentate gyrus, and cornu ammonis constitute the inner limbic arch and are connected by the fornices, whereas the outer limbic arch is composed of the subcallosal area, the cingulum, parahippocampal gyrus, and the uncus (19,20). Although the normal fornix is identifiable with routine MR imaging, the cingulum is not. The cingulum contains fibers of variable length that connect regions of the frontal and parietal lobes with temporal cortical regions and the cingulate gyrus (19). Thus, defects in the fornices and the cingulum potentially disrupt connectivity between the components of the inner and outer limbic arches; the exact clinical expression of this disruption is not known.

Our results indicate that the major white matter tracts of the limbic system, as seen with fiber tracking, were abnormal in 11 (85%) of 13 children with MM and Chiari II malformation. The fornices were abnormal in nine (69%) of 13 patients, and the cingulum was abnormal in 10 (77%) of 13 patients. In three patients, the cingulum was seen as crossing obliquely over the corpus callosum on FT reconstruction images, and the cingulum appeared to be composed of multiple parallel fiber bundles, an abnormality heretofore reported at postmortem analysis in case reports of patients with myelodysplasia (21). The aberrant fibers of the cingulum seen in some patients with MM and Chiari II malformation are presumed to represent disrupted neocortical axonal migration. This disrupted migration is possibly a related manifestation of lack of correct expression of cell adhesion molecules on neurons and is postulated to be the explanation for failure of closure of the neural tube (22). There was no relationship among the severity of the Chiari II malformation and the limbic abnormalities, as seen on FT reconstruction images, the position of the ventricular shunt, and the anomalies of the fornix or between the intactness of the fornices and a normal cingulum.

The defects observed in the fornices and the cingulum of most of the patients reported herein may be due to the destructive effects of hydrocephalus because all the patients in this study had hydrocephalus, and it was severe enough to require cerebrospinal fluid diversion in 12 of 13 patients. Patient 12 had ventriculomegaly with absence of signs of increased intracranial pressure; this patient had undergone prenatal closure of the posterior dysraphic defect. Beyond mechanical stretching of periventricular axons, chronic hydrocephalus has been shown to be associated with microvascular changes in the cerebral white matter, which include capillary compression and calcium-mediated proteolysis, that may account for the defects within the limbic fibers (23).

In nine patients with MM and Chiari II malformation who had undergone memory and learning testing, varying degrees of abnormalities of the fornix were seen in six (100%) of six patients with general memory deficits and four (100%) of four patients with learning deficits. Abnormalities of the cingulum were seen in four (67%) of six patients with general memory deficits and three (75%) of four patients with learning deficits. Statistically significant differences in overall general memory and learning scores between the patients with a normal fornix versus those with an abnormal fornix, as determined by using diffusion-tensor imaging, were not demonstrated. We acknowledge that such statistical analyses are exploratory and, given the small sample size (a limitation of our study), may or may not be generalized to the larger populations of all children with MM and Chiari II malformation. When the specific verbal and nonverbal memory tasks comprising the overall general memory index were independently assessed, statistically significant poorer performance for tasks involving nonverbal immediate recall was noted in the patients with anomalies of the fornix compared with those without them. No significant associations between abnormalities of the cingulum and performance for learning and memory tasks were observed.

Our findings are in accordance with the hypothesized role of the fornix as an important connecting structure of memory regions, particularly those related to visuospatial memory (24,25). Potential explanations for the lack of statistically significant associations between abnormalities of the cingulum and memory and learning performance may reflect low statistical power because of the small sample size. Alternatively, the abnormalities of the cingulum seen in the children with memory impairment may not be related to learning and memory issues per se but to other factors (eg, attention) that are known to be important prerequisites to learning and memory (17). Mild focused and sustained attention impairments have been documented in patients who have undergone cingulotomy (26). Although none of the children reported herein had a diagnosis of attention deficit disorder, mild to moderate impairment in focus was observed during testing in five of six children with memory disturbances. Finally, the assumption of a close relationship between learning and memory deficits and insult to a single neural structure (eg, the cingulum or fornix) in patients with MM and Chiari II malformation is likely to be an oversimplification, given the complex neural circuitry involved in memory and learning.

In conclusion, as seen with diffusion-tensor MR images and FT reconstruction images, limbic fiber abnormalities were common in our sample of patients with MM and Chiari II malformation. As further research on diffusion-tensor imaging and FT reconstruction emerges, a better understanding of the neuropathologic characteristics of individuals with MM and Chiari II malformation might be expected. Analyses of linkages between anatomic abnormalities and cognitive functions, such as intelligence, memory, language, and/or affect, must be conducted before we state that diffusion-tensor imaging and fiber tracking have any prognostic significance in patients with MM and Chiari II malformation.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors especially thank Cathy Halovanich, RT, for image acquisition.


   FOOTNOTES
 

Abbreviations: FT = fiber tract • MM = myelomeningocele

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; clinical studies, B.V., N.K.R.; statistical analysis, B.V.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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