Journal of the Neurological Sciences 165 (1999) 90–93 Vacuolating leukoencephalopathy with subcortical cysts with late onset athetotic movements a, b Jun-ichi Takanashi *, Katsuo Sugita , Yoichi Kohno a a b Department of Pediatrics, Faculty of Medicine, Chiba University, 1 -8 -1 Inohana, Chuo-ku, Chiba-shi, Chiba 260 -8677, Japan Department of Clinical Medicine, Faculty of Education, Chiba University, 1 -8 -1 Inohana, Chuo-ku, Chiba-shi, Chiba 260 -8677, Japan Received 14 August 1998; received in revised form 1 February 1999; accepted 15 March 1999 Abstract We reported a 10-year-old male with vacuolating leukoencephalopathy with subcortical cysts, who presented athetotic movements in the late stage. Magnetic resonance imaging demonstrated diffuse cerebellar white matter lesions, in addition to typical cerebral white matter abnormalities and characteristic subcortical cysts in the anterotemporal and parietal areas. Fluid-attenuated inversion recovery images are highly sensitive for the detection of subcortical cysts, which is essential for a diagnosis. This is most likely to be a severe form of vacuolating leukoencephalopathy with subcortical cysts, presenting with athetotic movements in the late stage.  1999 Elsevier Science B.V. All rights reserved. Keywords: Valuolating leukoencephalopathy with subcortical cysts; Magnetic resonance imaging; Fluid-attenuated inversion recovery; Athetosis; Child 1. Introduction A number of neurological disorders with onset in infancy are characterized by a combination of progressive neurological dysfunction, megalencephaly, and leukoencephalopathic changes on computed tomography or magnetic resonance (MR) imaging. Among them, Canavan disease and Alexander disease are best known. They are clinically severe, and diagnosed based on increased N-acetylaspartate in urine or on proton MR spectroscopy in patients with Canavan disease [1], and increased a B-crystallin and heat shock protein 27 in the cerebrospinal fluid in patients with Alexander disease [2]. Recently, van der Knaap et al. [3] reported eight children with new leukoencephalopathy, who had infantile onset megalencephaly, followed by delayed onset relatively mild motor deterioration with ataxia and spasticity, and typical MR imaging findings. According to the *Corresponding author: Tel.: 181-43-226-2144; fax: 181-43-2262145. E-mail address: jtaka@med.m.chiba-u.ac.jp (J. Takanashi) pathological findings [4], they named this syndrome vacuolating leukoencephalopathy with subcortical cysts (VLESC). We report the first Japanese case of VLESC with prominent cerebellar white matter involvement, who presented prominent athetotic movements in the late stage, and the availability of fluid-attenuated inversion recovery (FLAIR) images for a diagnosis. 2. Case report A now 10-year-old male was referred to Chiba University Hospital for evaluation of megalencephaly and psychomotor deterioration at the age of eight. He was born at 42 weeks gestation without pre- or perinatal difficulties, and his weight, height and head circumference were of the 50th percentile at birth. There was no family history of neurological illness. His development was normal for one year, i.e. smiling at two months, head control at three months, sitting alone at six months, standing up at nine months, uttering his first word at 12 months, and walking alone at 14 months. His head circumference began to increase after 0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00073-8 J. Takanashi et al. / Journal of the Neurological Sciences 165 (1999) 90 – 93 the age of six months. After two years, he showed an ataxic gait and tremor with a progressive increase in muscle tonus, and could not walk alone after six years. Generalized tonic clonic seizures commenced at the age of five years, and were successfully treated with valproic acid and carbamazepine. His developmental quotient (DQ) score was 97 at one-year-old, 53 at four-years-old, and 41 at eight-years-old. On the first admission at eight-years-old, his height was 116.0 cm (21.5 SD), weight 21.0 kg (21.2 SD), and head circumference 58.0 cm (14.0 SD). He could sit alone and crawl, but could not stand up or walk alone. The cranial nerves were intact. Cerebellar symptoms, such as truncal ataxia, dysmetria, tremor and slurred speech, were recognized. He also exhibited athetotic movements (irregular and writhing movements) of the distal upper limbs, and rigospastic quadriparesis with increased deep tendon reflexes and ancle clonus. Cranial MR imaging (Fig. 1) was performed with a 1.5 tesla superconducting imager (SIGNA Advantage, General Electric, Milwaukee, WI), which revealed diffuse T1 and T2 elongation in the cerebral and cerebellar white matter with sparing of deep white matter structures, such as the corpus callosum and internal capsules. We performed extensive laboratory studies, including on hematology, blood chemistry; serum very-long-chain fatty acids, amino acids; the activities of lysosomal enzymes, such as b-galactosidase, hexosaminidase A, galactosylceramidase, arylsulfatase-A; cell counts, protein, glucose, lactate, pyruvate, aB-crystallin and heat shock protein 27 in the cerebrospinal fluid; and metabolic screening of urine for amino acids, organic acids, and mucopolysaccharides; all of which were either within normal limits or negative. Brainstem auditory evoked potentials, flash-visual evoked potentials and motor nerve conduction velocities were all normal. Electroencephalogram showed independent sharp waves in the bilateral temporal regions. Fig. 1. MR imaging at eight-years-old. T2 weighted images revealed diffuse T2 elongation in the cerebral white matter with sparing of deep white matter structures, such as the corpus callosum and internal capsules. 91 On the second admission at 10 years, he showed truncal ataxia and progressive athetotic movements of the upper limbs. Tremor or dysmetria was not recognized. T1 and T2 weighted images showed T1 and T2 elongation in the cerebral and cerebellar white matter without obvious interval changes. FLAIR (Fig. 2A,B) revealed subcortical cysts in the left temporal and parietal regions, which could not be detected on T1 and T2 weighted images (Fig. 2C). From the laboratory data, we could rule out disorders with megalencephaly and leukoencephalopathy, such as Alexander disease, Canavan disease, L-2-hydroxyglutaric aciduria, glutaric aciduria type 1, sphingolipidosis, mucopolysaccharidosis and mitochondrial encephalopathy. Because of the infantile onset megalencephaly, delayed onset of motor dominant deterioration, and typical MR imaging findings, we diagnosed him as having VLESC. 3. Discussion van der Knaap et al. [3] reported eight children with megalencephaly and leukoencephalopathy, and a delayed onset of slowly progressive neurological dysfunction as ‘‘leukoencephalopathy with swelling and a discrepantly mild clinical course’’. The disorder probably has an autosomal recessive mode of inheritance, but no basic biochemical defect has not been identified. The histopathological findings revealed a spongiform leukoencephalopathy without cortical involvements [4]. Most vacuoles were covered by single five-layered membranes, representing single myelin lamella. The histopathological findings place the disease among the vacuolating myelinopathies, the possible pathophysiological mechanism being splitting of the outermost myelin lamella at the intraperiod line or disturbance of compaction of the outermost myelin lamella at the intraperiod line. Based on the pathological findings, they named the disorder VLESC [5]. In the original eight children with VLESC, the neurological findings were initially normal or near normal, despite megalencephaly with onset within one year. Slowly progressive ataxia and spasticity developed, while intellectual functioning was preserved for years after onset. Athetotic movements, which were observed in the late stage of this patient, i.e. six years after onset, were not described in the originally reported eight cases, although three of them had suffered for more than 10 years. Recently, Mejaski-Bosnjak et al. [6] also reported a case of VLESC, who presented choreoathetosis at 6 years of age. Athetotic movements are recognized in disorders with damage to striatal regions, such as Wilson disease and Hallervorden-Spatz disease, in which MR imaging revealed striatal lesions. However, the MR images in the present case demonstrated no abnormal signal intensity in the caudate nucleus or putamen. In Pelizaeus-Merzbacher 92 J. Takanashi et al. / Journal of the Neurological Sciences 165 (1999) 90 – 93 Fig. 2. MR imaging at 10-years-old. (A, B) FLAIR images revealed subcortical cysts in the left temporal and parietal regions (arrows), and high intensity lesions in the cerebellar white matter. (C) Subcortical cysts could not be recognized on T2 weighted images. disease (a rare dysmyelinating disorder affecting the central nervous system), in which MR images demonstrate diffuse white matter abnormality and no abnormal lesions in the striatal regions, choreiform or athetotic movements begin to appear later than abnormal eye movements in early infancy. Although the pathophysiological mechanism is uncertain, this case could be considered as a severe form of VLESC, presenting with athetotic movements in the late stage. The MR imaging abnormalities that are characteristic of VLESC are the discrepant severity in comparison with the clinical picture [3]. MR imaging revealed supratentorial, hemispheral white matter involvement with relative sparing of central white matter structures, the absence of any gray matter involvement, and the presence of subcortical cysts in the anterotemporal, fronto-parietal areas [3,5]. MR images of this patient demonstrated obvious bilateral cerebellar white matter lesions, in addition to typical cerebral white matter lesions and subcortical cysts. The cerebellar lesions, which were none or slight in the original eight cases [3], may explain more prominent cerebellar symptoms, such as truncal ataxia, dysrmetria, tremor, and slurred speech in our patient. FLAIR images, with which the signal from the cerebrospinal fluid is reduced and there is high T2 weighting for the brain, are reported to be more sensitive for detecting abnormal lesions than conventional T1 and T2 weighted images in many neurological disorders [7,8]. In the present case, subcortical cysts could not be recognized on conventional T1 and T2 weighted images at eight and 10 years because of the prominent T1 and T2 elongation in the surrounding white matter and contamination of the cerebrospinal fluid signal. Since subcortical cysts are radiologically essential for the diagnosis of VLESC, FLAIR images are strongly recommended for patients with diffuse leukodystrophy in order not to miss this disorder. J. Takanashi et al. / Journal of the Neurological Sciences 165 (1999) 90 – 93 Acknowledgements We wish to thank van der Knaap, MD for valuable radiological comments, and Fuminori Morita and Yoshitada Nakano for their excellent technical support. References [1] Austin SJ, Connelly A, Gadian DG, Benton JS, Brett EM. Localized 1 H NMR spectroscopy in Canavan’s disease: a report of two cases. Magnet Reson Med 1991;19:439–45. [2] Takanashi J, Sugita K, Yamada K, Tanabe Y, Niimi H. Adolescent case of Alexander disease: MR imaging and MR spectroscopy. Pediatr Neurol 1998;18:67–70. [3] van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts WFM, Hoogenraad F, Valk J. Leukoencephalopathy with 93 swelling and a descrepantly mild clinical course in eight children. Ann Neurol 1995;37:324–34. [4] van der Knaap MS, Barth PG, Vrensen GF, Valk J. Histopathology of an infantile-onset leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathologica 1996;92:206–12. [5] van der Knaap MS. New leukoencephalopathies. Eur J Paed Neurol 1997;1:A4. [6] Mejaski-Bosnjak V, Besenski N, Brockmann K, Pouwels PJW, Frahm J, Hanefeld FA. Cystic leukoencephalopathy in a megalencephalic child: clinical and magnetic resonance imaging / magnetic resonance spectroscopy findings. Pediatr Neurol 1997;16:347–50. [7] Thomas DJ, Pennock JM, Hajnal JV, Young IR, Bydder GM, Steiner RE. Magnetic resonance imaging of spinal cord in multiple sclerosis by fluid-attenuated inversion recovery. Lancet 1993;341:593–4. [8] Takanashi J, Sugita K, Fujii K, Niimi H. MR evaluation of tuberous sclerosis: increased sensitivity using FLAIR imaging and correlation with severity of seizures and mental retardation. Am J Neuroradiol 1995;16:1923–8.