Multiparametric MRI in a patient with adult-onset leukoencephalopathy with vanishing white matter A. Gallo, MD; M.A. Rocca, MD; A. Falini, MD; C. Scaglione, MD; F. Salvi, MD; A. Gambini, MD; L. Guerrini, MD; M. Mascalchi, MD, PhD; J.C. Pronk, PhD; M.S. van der Knaap, MD, PhD; and M. Filippi, MD Abstract—This is a multiparametric MR study of the first reported patient with adult-onset genetically confirmed vanishing white matter (VWM) disease. It shows that, despite the presence of a severe and diffuse damage of the brain WM, brain gray matter, and cervical cord tissue, the cortical adaptive capacities were relatively preserved. Interpatient variability of brain plasticity may contribute to the known phenotypic variation of patients with VWM disease. NEUROLOGY 2004;62:323–326 Leukoencephalopathy with vanishing white matter (LVWM) is a rare autosomal recessive disease, linked to mutations of genes encoding the five sub- units of the eukaryotic translation initiation factor eIF2B. 1,2 LVWM was defined as a separate entity on the basis of its peculiar MRI and proton MR spec- troscopy ( 1 H-MRS) features. 3 Typically, the disease begins during infancy or early childhood with a chronic progressive cerebello-pyramidal syndrome. 3,4 At present, only one case of symptomatic adult-onset LVWM, which was not genetically confirmed, 2,5 and two of asymptomatic adults with the mutation, 1,4 have been reported. We obtained multiparametric MR data from a woman with genetic and clinical findings consistent with a diagnosis of LVWM to estimate in vivo the extent of CNS pathology and the ability of the dis- eased brain to readapt following tissue injury in LVWM. Case report. A 52-year-old woman was admitted for a slowly evolving spastic tetraparesis associated with ataxia, dysarthria, and mental decline. Familial history was negative. She was healthy until age 25, when she developed paranoid behavior. Seven years later, she began to experience motor and cerebellar deficits. A diffuse slowing of the EEG and bilateral increased latencies of visual and acoustic evoked potentials were found. Nerve conduction velocity, EMG, and muscle and nerve biopsies were normal. The first MRI scan, obtained when she was 35, showed diffuse hyperintensity of the hemispheric white matter (WM) on dual-echo (DE) images with relatively low signal inten- sity of the globus pallidus. Follow-up MRI scans showed a progres- sive vanishing of the hemispheric WM. When she was 48, we performed a 1 H-MRS using a turbo spectroscopic imaging tech- nique. All the patient’s WM and gray matter (GM) voxels studied (14 voxels extracted from the periventricular and centrum semi- ovale WM and 2 voxels from the interhemispheric frontal and parietal cortices) showed a marked decrease of all metabolites compared to 12 age-matched controls. After an extensive metabolic screening for leukodystrophies on serum and urine, which was negative, a genetic analysis was performed, which showed homozygosity for the common missense mutation R113H in the EIF2B5 gene. 1 At this stage, the following MRI sequences were obtained from the patient and a group of eight age-matched controls: Brain—1) DE fast spin-echo; 2) fast– fluid-attenuated inversion recovery; 3) two-dimensional gradient echo (GE) with and without a saturation pulse to calculate magne- tization transfer ratios (MTR); 4) pulsed gradient spin-echo echop- lanar (EP) to calculate mean diffusivity (MD) and fractional anisotropy (FA); 5) three-dimensional–T1-weighted magnetization prepared rapid acquisition GE; 6) unlocalized 1 H-MRS 6 to obtain whole brain (WB) N-acetylaspartate (NAA) concentrations; 7) T2*- weighted single shot EP, during the performance of three motor tasks (tasks 1 and 2: flexion-extension of the last four fingers of the right/left hand; task 3: flexion-extension of the right foot). Motor functional assessment was performed at the time of MRI acquisition (upper limbs: nine hole peg test [9HPT] and maximum finger-tapping frequency; lower limb: maximum foot tapping fre- quency). The time to complete the 9HPT, as well as the finger and the foot tapping rates of the patient, were significantly different from those of controls; Cord—1) DE SE; 2) two-dimensional GE with the same parameters used for brain. Additional information about all the sequences is provided elsewhere. 7,8 MTR, MD, and FA maps and histograms were produced. 7 Us- ing circular regions of interest (ROI) 7 mm 2 in size, MTR, MD, and FA values were calculated for 12 areas of the hemispheric, noncystic WM and 18 areas of normal-appearing GM (NAGM). Cord MTR histograms were also obtained. 8 For each histogram, the average MTR, MD, and FA and the peak heights were mea- sured. WB NAA concentration was quantified as described else- where. 6 fMRI analysis was performed using statistical parametric mapping software (SPM99) and using as nuisance variable the results of the functional assessment tests in each subject to cor- rect for the different functional performances between the patient and controls. Results. Figure 1 depicts the major conventional brain MRI findings of this patient. No T2-visible abnormalities were detected in the cervical cord. From the Neuroimaging Research Unit, Department of Neurology (Drs. Gallo, Rocca, and Filippi) and Neuroradiology (Drs. Falini and Gambini), Scientific Institute and University Ospedale San Raffaele, Milan; Department of Clinical Neurology (Drs. Scaglione and Salvi), Ospedale Bellaria, University of Bologna; Radiodiagnostic Section (Drs. Guerrini and Mascalchi), Department of Clinical Physiopathology, University of Florence, Italy; and Departments of Clinical and Human Genetics (Dr. Pronk) and Child Neurology (Dr. van der Knaap), Free University Medical Center, Amsterdam, the Netherlands. Received July 17, 2003. Accepted in final form September 23, 2003. Address correspondence and reprint requests to Dr. Massimo Filippi, Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; e-mail: massimo.filippi@hsr.it Copyright © 2004 by AAN Enterprises, Inc. 323