Pediatric Neurology 53 (2015) 47e52

Contents lists available at ScienceDirect

Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu

Original Article

High-Resolution Diffusion Tensor Imaging and Tractography in Joubert Syndrome: Beyond Molar Tooth Sign Charlie Chia-Tsong Hsu MBBS a, Gigi Nga Chi Kwan MBBS a, Sandeep Bhuta MBBS, DNB, FRANZCR a, b, * a b

Department of Medical Imaging, Gold Coast University Hospital, Southport, Queensland, Australia Griffith University, School of Medicine, Southport, Queensland, Australia

abstract BACKGROUND: We undertook diffusion tensor imaging analysis of brainstem fiber tracts in two Joubert syndrome patients. METHODS: Two Joubert syndrome patients underwent magnetic resonance imaging brain examination with diffusion tensor imaging. Imaging findings were compared with five age- and sex-matched control subjects with approval from the institutional ethic committee. The medical history and clinical examination findings in both patients were documented. RESULTS: Diffusion tensor imaging analysis of the first patient demonstrated absence of the dorsal pontocerebellar tract and thinning of the middle cerebral peduncle. Diffusion tensor imaging analysis of the second child revealed thinning of the both the dorsal pontocerebellar and ventral pontocerebellar tract. Both patients exhibited thickened and horizontally oriented superior cerebellar peduncles. The superior cerebellar peduncles also failed to decussate in the mesencephalon. CONCLUSION: Pontocerebellar tract abnormalities in Joubert syndrome patients have not been previously recognized. The difference in the pontocerebellar tract between the two Joubert syndrome patients suggests a spectrum of severity of pontine axonal migration abnormality. Keywords: joubert syndrome, magnetic resonance imaging, diffusion tensor imaging

Pediatr Neurol 2015; 53: 47-52 Ó 2015 Elsevier Inc. All rights reserved. Introduction

Joubert syndrome is a rare disorder with an incidence of 1/80,000 to 1/100,000 live births.1,2 It is characterized by complex malformation of the midbrain-hindbrain, with the so-called molar tooth sign on axial imaging.3 This results from vermian hypoplasia, a deep interpeduncular fossa, and thickened, elongated, and abnormally horizontal superior cerebellar peduncles.3 Joubert syndrome is clinically characterized by hypotonia evolving into ataxia and developmental delay4 and is associated with the variable involvement of other organs and systems, mainly the eyes and kidneys.5 Genetic heterogeneity mirrors the clinical heterogeneity of Joubert syndrome.5 Radiologic-genotype Article History: Received November 25, 2014; Accepted in final form February 28, 2015 * Communications should be addressed to: Dr. Bhuta; Associate Professor and Neuroradiologist; Griffith University; School of Medicine; Department of Medical Imaging; 1 Hospital Boulevard; Gold Coast University Hospital; Gold Coast; QLD 4215, Australia. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.02.027

correlation in Joubert syndrome is difficult because of the low estimated prevalence.6 The morphological appearance in Joubert syndrome patients shows great variability, even among Joubert syndrome siblings. The largest imaging review of 75 Joubert syndrome patients found intrafamilial variability in imaging appearance on conventional magnetic resonance imaging (MRI) sequences and no distinct neuroimaging features between the genotypes.6 Diffusion tensor imaging (DTI) technique has given an insight into the underlying complex fiber tract abnormalities in Joubert syndrome. The concept of axonal migration and failure of decussation of fiber tracts in Joubert syndrome may be influenced by specific gene mutation, and it is plausible to speculate a possible correlation. The aim of the study was to evaluate the course of white matter tracts by performing DTI in two Joubert syndrome patients in comparison to age-matched controls. Patient and Materials Two children with Joubert syndrome after parental consent were recruited into the studyda 4-month-old boy (patient A) and a 10-year-old

48

C.C.-T. Hsu et al. / Pediatric Neurology 53 (2015) 47e52

TABLE. Distribution of Patients with Joubert Syndrome

Patients Age/sex

Clinical Presentation

A

4-month-old boy Oculomotor dyspraxia, (MRI with DTI ataxia and gross motor acquisition) developmental delay.

B

10-year-boy (MRI with DTI acquisition)

Medical History

Renal or Ocular Findings

Parental consanguinity. The child was Normal funduscopic examination. born at term by Cesarean section without Normal abdominal ultrasound with no complication. The parents recall hepatic or renal abnormalities. nystagmus being present in the first days of life.

Hypotonia, motor delay, ataxia, Normal term pregnancy and with no conjugate oculomotor apraxia neonatal complications. Retrospectively, the parents noted pauses and in coordination with his breathing during the first month.

Bilateral optic nerve hypoplasia and electroretinogram evidence of retinitis pigmentosa. Normal abdominal ultrasound with no hepatic or renal abnormalities.

Abbreviations: DTI ¼ Diffusion tensor imaging MRI ¼ Magnetic resonance imaging

FIGURE 1. In a healthy subject, axial color-coded fractional anisotropy map (A), tensor map (B) tractography superimposed on the anatomical dataset (C), and threedimensional tractography projection views (D, E) at the level of mid pons demonstrate normal laminar appearance of the major fiber tracts. 1 ¼ ventral pontocerebellar tract (red); 2 ¼ corticospinal tracts (blue); 3 ¼ dorsal pontocerebellar (red); 4 ¼ pontine tegmental tract (blue); 5 ¼ middle cerebral peduncle (green).

C.C.-T. Hsu et al. / Pediatric Neurology 53 (2015) 47e52

49

FIGURE 2. Patient A, axial color-coded fractional anisotropy map (A) and tensor map (B) at the level of mid pons demonstrate absence of the dorsal transverse pontine fiber. Fiber tractography superimposed on the anatomical dataset (C), and three-dimensional projections (D, E) also confirm the missing fiber tract. Numbers indicate: 1 ¼ ventral pontocerebellar tract (red); 2 ¼ corticospinal tracts (blue); 4 ¼ pontine tegmental tract (blue); 5 ¼ middle cerebral peduncle (green).

boy (patient B). Clinical data available for each patient are summarized in the Table above. Five age- and sex-matched (4 months, 6 years, 7 years, 8 years, and 10 years) patients were recruited as control subjects. Informed consent was received from all participants’ parents and all procedures were performed with the approval of the institutional review board for clinical studies. MRI was performed on a 1.5 T MRI system (Siemens Magnetom SymphonyTim syngo MR B18) and acquired the imaging with a standard 32-channel head coil. The 4-month-old child required general anesthetic sedation for the MRI examination. The 10-years-old patient was able to undergo MRI without sedation. A 4-month-old, age-matched control patient had general anesthetic sedation MRI in the context of

febrile seizures but otherwise was developmentally normal and had no medical conditions or family history of hereditary disease. This control patient had normal neurological examination assessed by a pediatric neurologist. The remaining four healthy control patients were able to undergo MRI without sedation. MRI-compatible video goggle aided with compliance. All control patients had the initial conventional MRI reviewed, which showed normal degree of myelination for age and no pathologic changes before DTI sequences were acquired. Before DTI measurement, we performed conventional multiplanar T2-weighted fast spin-echo and coronal T1-weighted spin-echo imaging sequences using standard departmental imaging protocols. We sampled

50

C.C.-T. Hsu et al. / Pediatric Neurology 53 (2015) 47e52

FIGURE 3. Axial color-coded fractional anisotropy map of control patient (A), patient B (B), and patient A (C) at the level of pons. VPC and DPC are identified as asterisks (*). In the normal subject (A), the VPC and DPC are seen as two parallel red fiber bundles with the CST sandwiched in between. In patient B (B), both VPC and DPC are abnormally thin. An additional red fiber bundle is seen between the CST. In patient A (C), the VPC is abnormally thickened but the DPC is absent. The typical molar tooth appearance can be appreciated in both Joubert syndrome patients as elongated and horizontally oriented SCP (B and C, arrows), which is in contrast to the short, vertically orientated SCP in the normal control (A, arrows). Color-coded FA maps of the midbrain in patient A (D) demonstrates the SCP assuming a more horizontal orientation (white arrows). This can be better appreciated on three-dimensional fiber tractography (E), with an arrow pointing to the thickened horizontally positioned SCP. Abbreviations: CST ¼ Corticospinal tracts; DPC ¼ Dorsal pontocerebellar; SCP ¼ Superior cerebellar peduncles; VPC ¼ Ventral pontocerebellar tract.

the diffusion tensor by repeating a diffusion-weighted single-shot spinecho echo-planar sequence along 30 different geometric directions. An effective b-value of 1000 s/mm2 was used for each of the 30 diffusionencoding directions and an additional measurement without diffusion weighting (b_0 s/mm2). Scan parameters were field of view 230, repetition time 3700 ms; echo time 105 ms, matrix size of 128. A total of 36 contiguous 4-mm-thick axial sections were acquired with coverage from skull vertex to the medulla. We generated isotropic diffusion-weighted images, apparent diffusion coefficient maps and color-coded fractional anisotropy (FA) maps using Siemens multimodality workstation. The three-dimensional orientation of the major eigenvector was color coded per voxel according to convention with red indicating the transverse (xelement), green indicating the anteroposterior (y-element), and blue indicating the craniocaudal (z-element) orientation of the anisotropic component of diffusion within each voxel. The color intensity scale was proportional to the measured FA value. Systematic analysis of the major fiber tracts of the brainstem was performed on a Siemens multimodality workstation. Color-coded FA maps were used to guide placement of the region of interest for fiber

tracking in each of the major fiber tracts at the mid-pons level of the midbrain including the corticospinal tracts, pontocerebellar tracts, pontine tegmental tracts, and the superior cerebellar peduncle.

Results

DTI analysis of normal control patients was helpful in understanding the normal laminar appearance of the pons with the vertically orientated corticospinal tracts (CST) interposed between the transverse orientated ventral pontocerebellar (VPC) and dorsal pontocerebellar (DPC) tracts. Fibers from both VPC and DPC contribute to the formation of the middle cerebellar peduncle (MCP). The pontine tegmental tract was situated posterior to the DPC. This laminar configuration can be appreciated on the axial FA texture and tensor map and tractography (Fig 1). Conventional MRI confirmed the classic molar tooth sign and

C.C.-T. Hsu et al. / Pediatric Neurology 53 (2015) 47e52

51

FIGURE 4. In patient B, color-coded FA (A) and texture maps (B) demonstrate the absence of the red dot sign and absence of decussation of the SCP. This is confirmed by fiber tractography (C). In a healthy patient, the decussation of the SCP is identified as a red dot (arrow) on the color-coded FA map (D) and texture map (E). Fiber tractography (F) again demonstrates decussation of the SCP and the red dot sign. Abbreviations: FA ¼ Fractional anisotropy; SCP ¼ Superior cerebellar peduncles.

bat’s wing shaped fourth ventricle in both patients. Patient A demonstrated absence of the DPC fibers and thinning of the medial fibers of the MCP (Fig 2). In patient B, both VPC and DPC tracts were present but both were abnormally thinned (Fig 3). DTI analysis of the midbrain in both patients A and B revealed horizontally oriented and thickened superior cerebellar peduncles (SCP) (Fig 3). This is in contrast to the vertically orientated and thin SCP in normal subjects. Normal decussation of SCP fibers at the level of the midbrain was observed in the normal control subjects, which constituted the normal “red dot” sign. In both patients, this characteristic red dot sign was absent (Fig 4). Discussion

Joubert syndrome is a rare autosomal recessive disorder representing one of the developmental defects of the cerebellar vermis. The neuroradiological hallmark of the

molar tooth sign has traditionally aided in the diagnosis. On conventional MRI, the brainstem of Joubert syndrome is dysmorphic in approximately 30% of patient, with reported abnormalities in the mesencephalon, superior cerebellar peduncles, fourth ventricle, and fastigium.7 Although the morphological abnormalities in Joubert syndrome have been well characterized on conventional MRI, recent case reports, and case series using DTI technique have unraveled fiber tract abnormalities not seen on conventional MRI.8e11 The normal appearance of the pontine white matter tract can be simplified on axial texture and tensor FA map as four major fiber tracts: VPC tract, CST, DPC tract and tegmental tract.12,13 The VPC and DPC tracts sandwich the CST and converge posteriorly to form the MCP. The fibers from the VPC and DPC tracts are positioned on the lateral and medial margins of MCP respectively.12 Patient A demonstrated complete absence of the DPC tract with thinning of the medial portion of the

52

C.C.-T. Hsu et al. / Pediatric Neurology 53 (2015) 47e52

corresponding MCP. Although VPC and DPC tracts were present in patient B, both these fibers were noticeably thinner compared with the control subjects. This finding suggested the possible spectrum of VPC and DPC abnormalities. Further probabilistic tractography study suggested that the VPC had preferential connection to the orbitofrontal and prefrontal cortices, while DPC received more widespread cortical connection.7 This altered connectivity has unknown implications and requires further research to elucidate. The axonal migration concept may assist in interpretation of the observed absence or thinning of the DPC tract and the compensatory thickening of the VPC.14e16 Abnormal decussation of the two fiber tracts SCP and CST have been described in Joubert syndrome.8,9,11 We were able to confirm the previously documented absence of SCP decussation in the midbrain characterized by the absence of the red dot sign in the interpeduncular fissure of the midbrain.8,9,11 The absence of SCP decussation and pontocerebellar fiber abnormalities are also seen in two other brainstem malformations: pontine tegmental cap dysplasia and horizontal gaze palsy with progressive scoliosis (HGPPS).14,15,17 Although these condition share minor overlapping features, pontine tegmental cap dysplasia can be distinguished from Joubert syndrome by the characteristic dorsal pontine vaulting with presence of ectopic commissural fibers and multiple cranial nerve neuropathies. HGPPS is caused by mutations in the ROBO3 gene located on chromosomes 11q23e25.17 Although HGPPS is not associated with the MRI molar tooth sign, HGPPS shares similar imaging features of absence of the SCP and the dorsal pontocerebellar fiber on DTI as also seen in Joubert syndrome.17 The overlapping imaging features of different congenital brainstem malformation suggests a “common morphologic pathway” for the various genetic mutations. However, HGPSS patients clinically have preserved motor and sensory functions and coordination and do not demonstrate the severe ataxia and apraxia as observed in Joubert syndrome.17 Conclusion

High-resolution DTI and tractography have added a new dimension in understanding of fiber tract abnormalities in Joubert syndrome. Absence and or thinning of the DPC tract and abnormal thickening of the VPC tract are novel findings in Joubert syndrome and have not been previously described in the literature. In addition, abnormal

decussation of superior cerebellar peduncles and absence of red dot sign is a further indication that they represent a spectrum of abnormal midline axonal migration.

References 1. Parisi M, Doherty D, Chance P, et al. Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet. 2007;15:511-521. 2. Kroes H, van Zon P, Fransen van de Putte D, et al. DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands. Eur J Med Genet. 2008;51:24-34. 3. Maria B, Quisling R, Rosainz L, et al. Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance. J Child Neurol. 1999;14:368-376. 4. Joubert M, Eisenring J, Robb J, et al. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnoea, abnormal eye movements, ataxia, and retardation. Neurology. 1969;19:813-825. 5. Valente E, Brancati F, Dallapiccola B. Genotypes and phenotypes of Joubert syndrome and related disorders. Eur J Med Genet. 2008;51: 1-23. 6. Poretti A, Huisman T, Scheer I, et al. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol. 2011;32:1459-1463. 7. Alorainy I, Sabir S, Seidahmed M, et al. Brain stem and cerebellar findings in Joubert syndrome. J Comput Assist Tomogr. 2006;30: 116-121. 8. Poretti A, Boltshauser E, Loenneker T, et al. Diffusion tensor imaging in Joubert syndrome. AJNR Am J Neuroradiol. 2007;28:1929-1933. 9. Widjaja E, Blaser S, Raybaud C. Diffusion tensor imaging of midline posterior fossa malformations. Pediatr Radiol. 2006;36:510-517. 10. Lee S, Kim D, Kim J, et al. Diffusion-tensor MR imaging and fiber tractography: a new method of describing aberrant fiber connections in developmental CNS anomalies. Radiographics. 2005;25: 53-65. discussion 66e8. 11. Merlini L, Vargas M, De Haller R, et al. MRI with fibre tracking in Cogan congenital oculomotor apraxia. Pediatr Radiol. 2010;40:1625-1633. 12. Habas C, Cabanis E. Anatomical parcellation of the brainstem and cerebellar white matter: a preliminary probabilistic tractography study at 3 T. Neuroradiology. 2007;9:849-863. 13. Terajima K, Matsuzawa H, Shimohata T, et al. Tract-by-tract morphometric and diffusivity analyses in vivo of spinocerebellar degeneration. J Neuroimaging. 2009;19:220-226. 14. Jissendi-Tchofo P, Doherty D, McGillivray G, et al. Pontine tegmental cap dysplasia: MR imaging and diffusion tensor imaging features of impaired axonal navigation. AJNR Am J Neuroradiol. 2009;30: 113-119. 15. Barth P, Majoie C, Caan M, et al. Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. Brain. 2007;130:2258-2266. 16. Engle E. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol. 2010;2:a001784. 17. Sicotte N, Salamon G, Shattuck D, et al. Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations. Neurology. 2006;67:519-521.

High-Resolution Diffusion Tensor Imaging and Tractography in Joubert Syndrome: Beyond Molar Tooth Sign.

We undertook diffusion tensor imaging analysis of brainstem fiber tracts in two Joubert syndrome patients...
3MB Sizes 1 Downloads 13 Views