MR imaging and spectroscopy in juvenile Huntington disease

Pediatr Radiol (2004) 34: 640–643 DOI 10.1007/s00247-004-1159-y Mark Schapiro Kim M. Cecil Jason Doescher Alaina M. Kiefer Blaise V. Jones Received: 24 November 2003 Revised: 29 December 2003 Accepted: 2 February 2004 Published online: 23 March 2004 Ó Springer-Verlag 2004 This work was funded in part by NIEHS P01 ES011261 (Dr. Cecil) M. Schapiro Æ J. Doescher Division of Neurology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA K. M. Cecil (&) Æ A. M. Kiefer Imaging Research Center, Departments of Radiology and Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA E-mail: Kim.Cecil@cchmc.org Tel.: +1-513-6368559 Fax: +1-513-6363754 CASE REPORT MR imaging and spectroscopy in juvenile Huntington disease Abstract Juvenile Huntington disease manifests differently from adult Huntington disease and has more variability in presentation. We describe a child with cognitive decline and adventitial movements in whom Huntington disease was confirmed with genetic testing. MR imaging showed abnormal T2 prolongation in the putamina and progressive caudate atrophy, and MR spectroscopy revealed elevated myoinositol and diminished N-acetyl aspartate, creatine, and phosphocreatine. Imaging findings of caudate atrophy and abnormal T2 prolongation in the putamina with MR spectroscopy findings consistent with dense gliosis can be helpful indicators of juvenile Huntington disease. Keywords Juvenile Huntington disease Æ MR imaging Æ Spectroscopy B. V. Jones Division of Neuroradiology, Department of Radiology and Pediatrics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA Introduction Juvenile Huntington disease (JHD), which comprises only a small percentage of all cases of Huntington disease (HD), manifests differently from adult HD. Further, there is more variability in onset, with presentation in the first decade often differing from that in the second decade [1]. Though genetic testing may be ethically performed in children presenting with a positive family history and a typical clinical profile, it is less clear whether to test children with variations in presentation. As the long-term prognosis and length of survival are 641 calculated based upon the time of diagnosis, one does not want to do genetic testing prematurely because of medical and psychosocial consequences [1]. It has not been established whether neuroimaging will be helpful in determining onset of disease activity in children. We had the opportunity to use MRI/MRS to study a child with cognitive decline and adventitial movements without a known family history of HD, in whom HD was later confirmed with genetic testing. Case report An 8-year-old male was referred to the Division of Neurology for evaluation of developmental delay and clumsiness. Though he walked at 14 months, he was delayed in speaking, with his first appropriate words at 3.5 years of age. He was always described as ‘‘clumsy.’’ He had attended special education classes since entering school. The past history revealed a pregnancy complicated by gestational diabetes leading to a birth weight of 7 lb 4 oz at 38 weeks’ gestation. There were no perinatal or neonatal complications. At 7 weeks of age, he had a generalized tonic-clonic seizure; workup reportedly showed a normal brain CT scan and EEG. No further seizures occurred. Family history was notable for several maternal family members with developmental delay of unknown etiology, and 2 older male siblings described as ‘‘mildly to moderately delayed.’’ His father was reported as having limited contact with the family owing to ‘‘personal behavioral problems.’’ Examination showed that he spoke in simple phrases with much effort. He had slight unsteadiness of gait and decreased fine motor movements on the left. At a follow-up visit 2 years later, he was reported to have decreased endurance, with more falls, increased slurring of speech, difficulty finding words, and slow production of sentences. Mild choreoathetoid movements were seen on physical examination. Examination 2 years subsequent identified dysarthric speech, with mild-to-moderate chorea of his extremities. There were some athetoid movements of his trunk, exacerbated during ambulation. He had a darting tongue, but no milkmaid grip. Deep tendon reflexes were 2/4, with no Babinski sign. Initial MR imaging at 6 years 8 months of age was unremarkable. A follow-up MR examination at 9 years 11 months of age showed a definite loss of volume in the head of the caudate nuclei, with development of abnormal T2 prolongation in the putamina, which also demonstrated volume loss (Fig. 1). The imaging findings were not significantly changed on the third MR examination performed 1 year later. Bilateral MR spectroscopy was performed at the time of the second and third MR examinations, evaluating single voxels (volume measured 8 cm3) centered in the basal ganglia (Fig. 2). Point-resolved spectroscopy (PRESS) localization was employed, with a short echo time (TE) of 35 ms and a repetition time (TR) of 2,000 ms. Long echo time spectra were acquired unilaterally (left) for each examination using a TE of 288 ms and TR of 2,000 ms. Commercially available software for spectroscopic quantitation known as LC Model [2] was used to calculate metabolite concentrations. A confidence interval for each metabolite was determined with control data. Z-scores were calculated and evaluated for statistical significance. The spectra showed elevated levels of myoinositol (mI) relative to age-matched normals (n=33, 24 male), a relative reduction in the resonances corresponding to creatine and phosphocreatine (Cr), and a statistically insignificant reduction of N-acetyl aspartate (NAA) (Table 1). There was no lactate peak. Genetic testing for HD showed 84 CAG repeats at HD allele 1 and 15 CAG repeats at HD allele 2. Fig. 1 Axial FLAIR image centered at the level of the basal ganglia shows marked volume loss in the head of the caudate nucleus on both sides and abnormal hyperintense signal in the putamina (long arrows) Discussion Juvenile Huntington disease is the term used to describe the 1–6% of patients with HD that present during childhood rather than the fourth to fifth decade. Previous reports have identified an earlier onset of symptoms in patients whose fathers have HD, as opposed to those whose mothers are affected. A larger number of cytosine-adenine-guanine (CAG) repeats in the unstable DNA segment associated with HD has been correlated with an earlier onset of disease [3]. As such, JHD appears to represent a more pronounced manifestation of the same disease process that is seen in adult onset HD. On imaging, HD is classically recognized as causing atrophy of the caudate nuclei. This atrophy can be quantified by measurement of the distance between the caudate heads and calculation of a ratio by dividing this distance by the width of the inner table, termed the bicaudate ratio. Comparison of such ratios among JHD, normals, and children with other disease processes affecting the basal ganglia shows a significant segregation of JHD [4]. As these ratios are not routinely calculated in all children undergoing imaging, it is difficult to say whether they provide a basis for a more sensitive detection of JHD early in the course of the disease. In the presented case, the bicaudate ratio on the first MR examination was 0.13. On subsequent 642 Fig. 2 Single voxel proton MR spectroscopy performed on the tissue included in the white square. Patient spectra were notable for elevation of the myoinositol resonance and reduction of the creatine and N-acetyl aspartate resonances Table 1 Metabolite concentrations (mM) measured by proton MR spectroscopy at second and third MR examinations. Single voxel MRS sampling in the right basal ganglia Metabolite 9 years 10 years Control values (n=33) NAA Cr Cho mI 6.81 4.25* 1.26 4.29** 6.92 4.49** 1.21 4.35** 8.05±0.90 5.88±0.72 1.25±0.20 2.94+0.74 Confidence Intervals 7.74, 5.64, 1.18, 2.67, 8.36 6.13 1.31 3.18 *P=0.012 and **P=0.03 for creatine and myo-inositol examinations, the bicaudate ratio was measured at 0.21 and 0.23. Ho [4] reported a bicaudate ratio of 0.093±0.068 in normals, and we found a mean bicaudate ratio of 0.08 ±0.02 in a population of age- and gender-matched controls. The abnormal signal seen in the putamina in the presented case is a finding that has been more commonly reported in JHD than in adult-onset HD. Ho reported this finding in the three patients in the series that underwent MR imaging, and Mirowitz et al. reported it in two [4, 5]. While volume loss in the caudate nuclei is the most readily recognized imaging finding in both adult-onset and juvenile HD, more extensive loss of cerebral volume has been reported [6], and there may be a correlation between degree of striatal volume loss and extent of CAG repeats on genetic analysis [7]. Volume loss and signal abnormality in the basal ganglia are not specific findings for juvenile HD, however. In the pediatric population mitochondrial encephalopathies, Hallervorden-Spatz disease, Wilson disease, carbon monoxide poisoning, ethylene glycol ingestion, and infectious encephalopathies can all present with symmetric signal abnormalities in the basal ganglia, with or without detectable loss of volume. There are limited studies of HD employing magnetic resonance spectroscopy, and to our knowledge, none of the juvenile variant. Reports of MR spectroscopy in adult-onset HD vary, with several reporting the detection of increased lactate [8, 9]. In our patient, there was no evidence of lactate upon short or long echo spectroscopy in either hemisphere on either examination. Reduction in NAA and elevation of myoinositol in this case can reasonably be inferred from the prior literature to reflect dense gliosis within the striatum, and the creatine and phosphocreatine decrease relative to normal suggests a defect in energy metabolism accompanied by neuronal loss as evidenced by the NAA decline. The control data were predominantly obtained in the left basal ganglia, including the caudate and putamen, typically having less thalamic inclusion than the voxels used in our patient. Comparison of the metabolite concentrations obtained on the two MRS examinations performed in the left basal ganglia in this case showed an interval 9% reduction of creatine, a 6% reduction of N-acetyl aspartate, and a 9% elevation of myoinositol, while choline levels remained constant. Right basal ganglia metabolite changes between the two examinations were less than 5%, but the deviation from control concentrations was slightly greater. Reports in adults have suggested that brain creatine levels may be an indicator of disease progression and/or response to treatment with agents such as co-enzyme Q10 and creatine supplementation [10, 11, 12]. The case presented exemplifies the variability in both the clinical and MR imaging presentation of JHD. Both the imaging abnormalities and MRS findings in this case can be seen in other pathologies. However, the combination of caudate atrophy, putaminal signal abnormality, and MRS evidence of gliosis all indicate that active disease was occurring in this patient. These findings can lead to confirmation of the diagnosis with genetic testing. In addition, MR spectroscopy indicated a progression of pathology in the absence of changes detected by imaging alone. This supports the concept of using MRS as a means for following disease progression or response to treatment. 643 References 1. Nance MA, US Huntington Disease Genetic Testing Group (1997) Genetic testing of children at risk for Huntington’s disease. Neurology 49:1048–1053 2. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679 3. Lucotte G, Turpin JC, Riess O, et al (1995) Confidence intervals for predicted age of onset, given the size of (CAG)n repeat, in Huntington’s disease. Hum Genet 95:231–232 4. 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