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Year : 2006  |  Volume : 9  |  Issue : 3  |  Page : 172-174

Vanishing white matter disease: Phenotypic, MR imaging and 1H spectroscopic observations

1 Department of Neuroimaging and Interventional Neuroradiology, National Institute of Mental Health and Neurosciences, Bangalore, India
2 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India

Correspondence Address:
S Sinha
National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore - 560 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-2327.27662

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We report MR imaging features of vanishing white matter disease in a 7-year-old boy, who manifested with seizures, aphasia, spastic quadriparesis and myoclonic jerks. MRI of brain showed diffuse white matter signal changes of CSF intensity in all the sequences. MR spectroscopy of white matter showed severe decrease in NAA, choline and creatine and presence of lactate peak. Additional notable findings were diffuse extensive brain stem and thalamic atrophy. The clinico-radiological correlation was consistent with the diagnosis of vanishing white matter disease. Reporting of such cases may widen the spectra of these disorders.

Keywords: MRI, MRS, myoclonic jerks, vanishing white matter disease

How to cite this article:
Ravishankar S, Sinha S, Taly A B, Panicker J. Vanishing white matter disease: Phenotypic, MR imaging and 1H spectroscopic observations. Ann Indian Acad Neurol 2006;9:172-4

How to cite this URL:
Ravishankar S, Sinha S, Taly A B, Panicker J. Vanishing white matter disease: Phenotypic, MR imaging and 1H spectroscopic observations. Ann Indian Acad Neurol [serial online] 2006 [cited 2022 Jul 5];9:172-4. Available from:

  Introduction Top

Vanishing white matter disease is a recently described rare leukoencephalopathy that was initially called 'childhood ataxia with central nervous system hypomyelinization (CACH).'[1],[2] The disorder was subsequently described in children as 'leukoencephalopathy' with vanishing white matter.[3],[4] The disease has an autosomal recessive mode of inheritance.[1],[2],[3],[4] Normal development in early childhood with progressive ataxia and spastic diplegia after trauma or infection is typical clinical presentation. MRI shows diffuse white matter signal changes of CSF intensity in all the pulse sequences with sparing of gray matter. MRS features are unique with severe decrease in NAA, choline and creatine With prominent lactate and glucose peaks.[1],[5] We describe the phenotype and MR imaging and spectroscopic features of vanishing white matter disease in view of its rarity.

  Case Report Top

This patient was a 7-year-old boy, fourth of four siblings, born of distant consanguineous parentage with a normal birth and initial developmental history. He was brought for loss of acquired motor and mental milestones since the age of three, stiffness of limbs followed by recurrent seizures and myoclonic jerks. One of his elder sib had died at 8 years of age and had similar symptoms but details were not available. He was emaciated and had a head circumference of 52 cm. Ocular fundi were normal. He had gross spasticity and brisk tendon reflexes in all four limbs and a bilateral extensor plantar response. Hemogram and routine serum biochemical tests, including hepatic and renal functions, electrolytes and serum lactate, were normal. Urine analysis was negative for abnormal metabolites including metachromatic granules. Serum levels of arylsulphatase A and B were normal. Motor and sensory nerve conduction parameters were within normal limits. EEG showed slow background activity. Ultrasound examination of abdomen was normal. Molecular diagnosis could not be performed.

MRI [Figure - 1] a-d revealed bilateral symmetrical diffuse extensive signal changes in white matter similar to that of CSF signal intensity in all lobes on T1W (hypointense), PD (hypointense), FLAIR (hypointense) and T2W (hyperintense) images with a very thin boundary between CSF and white matter [Figure - 1]b. There was diffuse involvement of deep and subcortical white matter, arcuate fibers, internal capsules, external capsule and corpus callosum. The cerebral cortex was thin with normal sulcal and gyral pattern. Thalamus on either side was atrophic. There was severe brain stem and cerebellar atrophy. Ventricles were dilated, likely due to white matter changes. A cavum septum pellucidum was noted. Basal ganglia were normal. In vivo localized multi-voxel proton spectrometry was done (Hybrid 2D chemical shift imaging; TE = 135 ms) from the white matter and cerebral cortex. The MRS of white matter showed severe decrease in NAA. Lactate peak was also noted [Figure - 1]e. MRS of cerebral cortex showed normal spectral pattern.

  Discussion Top

Leukoencephalopathy with vanishing white matter is a progressive cavitating disease of central white matter, which has been recently described by van der Knaap et al.[3],[4] The onset, although extremely variable, is common in childhood. The course is often relentlessly progressive with fluctuations.[2],[3] But both early and late onset and a relatively slow progression are known to occur.[4],[6],[7] Mutations in any of the five genes encoding the five subunits of eukaryotic initiation of translation factor EIF2B cause vanishing white matter.[8],[9] Mutations in the same genes have been observed in late onset vanishing white matter disease, Cree leukoencephalopathy and ovarioleukodystrophy.[10],[11] The disease is thought to be primarily axonal rather than demyelination, myelin being affected secondarily. Pathological study had shown axonal loss, hypomyelination, demyelination and gliosis, primarily involving the white matter with cortical sparing. Abnormal foamy oligodendroglial cells are identified and are unique for vanishing white matter.[12] Pontine tegmental white matter may also be involved.[3],[8] Increased cerebrospinal glycine level is noted and may be secondary to excitotoxic brain damage.[13]

The classical phenotype is a child with normal initial growth and milestones and later development of progressive ataxia and spasticity, provoked by fever, infection or minor head trauma. In later stages, dysarthria, bulbar symptoms, optic atrophy and epilepsy may manifest but are not predominant.[3],[8] Death may occur in a few months to many years. Late childhood or adolescent milder variants and vanishing white matter with ovarian failure (ovarioleukodystrophy) have been described.[11] Our patient had an AR pattern of inheritance and had classical clinical features. Myoclonic jerks noted in this patient have not been described earlier, to the best our knowledge.

Diagnostic criteria for diagnosing this disease include normal initial psychomotor development, deterioration following infection or trauma, presence of ataxia and spasticity with MR features of diffuse white matter signal changes with signal intensity of CSF on all pulse sequences.[1],[3],[4] Additional features are lesions in central tegmental tracts and basis pontis. Subcortical white matter involvement is early and severe. Cerebellar or primary vermian atrophy has been documented with or without involvement of cerebellar white matter. Basal ganglia are typically spared.[3] Internal and external capsules may also be spared. MRS might reveal reduced NAA, choline and creatine with mildly increased lactate and glucose peaks. In advanced disease, the white matter shows almost complete disappearance of all normal signals and presence of glucose and lactate, compatible with presence of mainly CSF and little brain tissue. Spectra of the cortex are preserved; however, signals representing lactate and glucose are described.[1],[5] Differential diagnosis on MR imaging include megalencephalic leukoencephalopathy with subcortical cysts, Canavan's disease and Alexander's disease.[14] Age of onset and temporo-frontal cysts differentiate it from megalencephalic leukoencephalopathy;[15],[16] classical phenotype of Canavan's disease along with MRS revealing elevated NAA and of Alexander's disease along frontal changes would exclude it.[16] The MRI in our patient revealed characteristic findings and thalamic atrophy, which have not been reported earlier.

Despite being rare and a newly described entity, vanishing white matter disease might be diagnosed by its phenotypic and MR imaging features.

  References Top

1.Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen HJ, Frahm J. Diffuse white matter disease in three children: An encephalopathy with unique features on MRI and MRS. Neuropediatrics 1993;24:244-8.  Back to cited text no. 1  [PUBMED]  
2.Schiffmann R, Moller JR, Trapp BD, Shih HH, Farrer RG, Katz DA, et al . Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994;35:331-40.  Back to cited text no. 2    
3.van der Knaap MS, Barth PG, Gabreels FJ, Franzoni E, Begeer JH, Stroink H, et al . A new unknown leukoencephalopathy with vanishing white matter. Neurology 1997;48:845-55.  Back to cited text no. 3    
4.van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998;51:540-7.   Back to cited text no. 4    
5. Tedeschi G, Schiffmann R, Barton NW, Shih HH, Gospe SM Jr, Brady RO, et al . Proton magnetic resonance spectroscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination. Neurology 1995;45:1526-32.   Back to cited text no. 5    
6.van der Knaap MS, van Berkel CG, Herms J, van Coster R, Baethmann M, Naidu S, et al . eIF2B-related disorders: Antenatal onset and involvement of multiple organs. Am J Hum Genet 2003;73:1199-207.   Back to cited text no. 6    
7. Prass K, Bruck W, Schroder NW, Bender A, Prass M, Wolf T, et al . Adult onset Leukoencephalopathy with vanishing white matter presenting with dementia. Ann Neurol 2001;50:665-8.  Back to cited text no. 7    
8.van der Knaap MS, Leegwater PA, Konst AA, Visser A, Naidu S, Oudejans CB, et al . Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 2002;51:264-70.   Back to cited text no. 8    
9.Leegwater PA, Vermeulen G, Konst AA, Naidu S, Mulders J, Visser A, et al . Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 2001;29:383-8.  Back to cited text no. 9    
10.Fogli A, Wong K, Eymard-Pierre E, Wenger J, Bouffard JP, Goldin E, et al . Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol 2002;52:506-10.  Back to cited text no. 10    
11.Fogli A, Rodriguez D, Eymard-Pierre E, Bouhour F, Labauge P, Meaney BF, et al . Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003;72:1544-50.   Back to cited text no. 11    
12.Wong K, Armstrong RC, Gyure KA, Morrison AL, Rodriguez D, Matalon R, et al . Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome. Acta Neuropathol (Berl) 2000;100:635-46.  Back to cited text no. 12    
13.van der Knaap MS, Wevers RA, Kure S, Gabreels FJ, Verhoeven NM, van Raaij-Selten B, et al . Increased cerebrospinal fluid glycine: A biochemical marker for a leukoencephalopathy with vanishing white matter. J Child Neurol 1999;14:728-31.  Back to cited text no. 13    
14.Senol U, Haspolat S, Karaali K, Luleci E. MR imaging of vanishing white matter. AJR Am J Roentgenol 2000;175:826-8.   Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Chandrashekar HS, Guruprasad AS, Jayakumar PN, Srikanth SG, Taly AB. Megalencephalic leukoencephalopathy with subcortical cysts: MRI and proton spectroscopic features. Neurol India 2003;51:525-7.  Back to cited text no. 15    
16.Edwards-Brown MK, Bonnin JM. White matter diseases. In : Atlas SW, editor. Magnetic resonance imaging of the brain and spine, 2nd ed. Lippincott-Raven: Philadelphia; 1996. p. 649-706.  Back to cited text no. 16    


[Figure - 1]

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