Diffuse White Matter Disease in Three Children: An Encephalopathy with Unique Features on Magnetic Resonance Imaging and Proton Magnetic Resonance

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1 244 Diffuse White Matter Disease in Three Children: An Encephalopathy with Unique Features on Magnetic Resonance Imaging and Proton Magnetic Resonance Spectroscopy By F. Hanefeld l, u. Holzbach l, B. Kruse l, E. Wilichowski l, H.]. Christen l and]. Frahm 2 labt. Kinderheilkunde, Schwerpunkt Neuropädiatrie, Georg-August-Universität, Göttingen, Germany, and 2Biomedizinische NMR GmbH, Max-Planck-Institut für biophysikalische Chemie, Göttingen, Germany Abstract Amongst21 childrenwith unclassified white matter diseases three patients could be characterised by an identical clinical picture, magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) findings as a probably distinct entity. Following anormal early development they later showed rapidly progressive motor symptoms (ataxia, spasticity) leading to severe handicap within one or two years after onsel. Later on bulbar symptoms, optic atrophy and epileptic seizures occurred. The MRI showed a diffuse homogenous hypodensity of the white matter almost identical to the signal of the ventricles. MRS revealed a near total absence of N-acetylaspartate, choline and creatine and an increase of lactate and glucose. One girl and oneboywere siblings, indicating an autosomal recessive trail. Keywords Progressive leukoencephalopathy - Autosomal recessive - Magnetic resonance imaging - Magnetic resonance spectroscopy MRI MRS VOI Tl FLASH T2 CE-FAST TE STEAM TR CCT Cr Cho Ins Glc NAA Lac CSF VLCFA Abbreviations magnetic resonance imaging magnetic resonance spectroscopy volume-of-interest spin-lattice relaxation time fast low angle shot spin-spin relaxation time contrast-enhanced Fourier acquired steady-state echo time stimulated echo acquisition mode repetition time cranial computed tomography creatine and phosphocreatine choline-containing compounds myo-inositol glucose N -acetylaspartate lactate cerebro-spinal fluid very long chain fatty acids Introduction White matter disease in childhood may reflect hypomyelination, dysmyelination or demyelination. The best known group are the leukodystrophies, genetic diseases, classified according to known enzymatic defects e.g. Krabbe's leukodystrophy (galactocerebrosid-ß-galactosidase deficiency) or according to pathology, particulary staining of myelin breakdown products (e.g. orthochromatic leukodystrophy) (6, 9). The introduction of magnetic resonance imaging has revolutionized the evaluation of cerebral disorders, Received September 6, 1993; accepted September 9, 1993 Neuropediatrics 24 (1993) Hippokrates Verlag Stuttgart particulary of white matter (1). In addition localized proton magnetic resonance spectroscopy allows the acquisition of in vivo spectra with an increasing number of metabolites to assess alterations of cerebral metabolism. As part of an ongoing study of progressive encephalopathies in childhood 61 children with diffuse white matter diseases have so far been studied by combined MRI and MRS, including 20 patients with adrenoleukodystrophy and 8 with metachromatic leukodystrophy (2, 7). In 21 children with diffuse white matter disease no classification was possible using biochemical, genetic, neurophysiological, morphological orneuroimaging techniques. Among these 21 unclassified cases with white matter disease there are three patients who share clinical features and unique MRI andmrs findings, whichjustified their separation into a new group of white matter disease so far notdescribed intheliterature. Two siblings (brotherand sister) and one female child have been studied so far.

2 White Matter Disease: MRI and MRS Neuropediatrics 24 (1993) 245 Methods Magnetic resonance studies were performed at 2.0 Tesla (Siemens Magnetom, Erlangen, Germany) using the standard imaging headcoil for MRI and MRS. For clinical MRI and selection of the volumes-of-interest (VOIs) T1-weighted FLASH images and in addition in Case 3 T2-weighted CE FAST images were used (4). VOIs located in parietal "white matter" had the size of 8 cm 3 in Case 2 and 12 cm 3 in Case 3. Localized proton MRS were acquired by means of a shortechotime (TE 20 ms) STEAM sequence using a repetition time of TR = 3000 ms and 128 accumulations. Technical details are given elsewhere (3). Both patients were mildly sedated by oral application of chloral hydrate (60 mg/kg b.w.). Prior to the investigations a written informed consent of the parents was obtained. Case reports Case 1 This boy was born in 1982 after an uneventful pregnancy. Following anormal neonatal period he was able to walk freely at 12 months and showed a normal speech and intellectual development. He suffered a commotio cerebri aged 1 year and remained healthy until the 15th of May 1985 (aged 3 years). At that day he suffered a mild head trauma falling to the ground whilst playing football. He remaind conscious but persistent ataxia was noticed for three days. A CCT (Fig. 1) showed diffuse hypodensities of the white matter. Further investigations revealed no abnormalities. TheCSF-proteinwas inthe upper normal limit (38 mg/dl). A lysosomal, peroxisomal or mitochondrial disorder could be excluded. Nerve conduction velocity was normal. During the following 6 months his condition remained stable, however, ataxia and tremor persisted and got worse following mild head traumas. He was therefore refered for examination at the age of 4 years. His physical state and skin were normal, there was no organomegaly. He was fully alert and seemed intellectually normal. He showed a spastic atactic gait. His museie tone was low with brisk reflexes, cloni and upgoing plantar reflexes. His speech was dysarthric, the masseter reflex brisk. He had full eye movements, no nystagmus and his fundi were normal. The following investigations were normal: lysosomal enzymes, VLCFA, phytanic acids, aminoand organic acids, lactate and plasma cortisol. Repeated neuroimaging showed identical white matter changes without signs of obvious cerebral atrophy. During the following months he developed marked spasticity, optic atrophy, swallowing difficulties and major seizures. He is now severely disabled, wheel chair bound and needs tube feeding. However his alertness is striking. Fig. 1 CCT of Patient 1 at the age of 3 years. was spastic-atactic with extensor plantar reflexes. She had mild dysarthria, but normal cranial nerve findings and a weil preserved intellectual capacity. At present she is also severely handicapped. Investigations for known lysosomal, peroxisomal and mitochondrial disorders were negative. Amino acids and organic acids, immunoglobulins and lactate were normal and infectious disorders, particulary Lyme disease, were excluded. In addition to the CCT combined MRI and MRS were performed. Case2 This girl, the sister of Patient 1, was born in Her early history was as uneventful as her brother's. No neurological abnormality could be detected in her, when his illness started. For ethical reasons no neuroimaging was performed at that time. In November 1986 (aged 2 years) she was in a healthy unremarkable condition, but was unable to stand one morning. Following a slight improvement she showed a clinical picture and course identical to her brother's. Her gait Fig.2 MRI of Patient 2 at the age of 5 years.

3 246 Neuropediatrics 24 (1993) F. Hanefeld et al ale Lae n Case 2 Control Fig.3 MRS from white matter of Patients 2,3 and a 9 year-old contra\. The MRI on T1-weighted images revealed diffuse, confluent white matter ahnormalities with a signal intensity almost identical to that of the ventricles (Fig. 2). Figure 3 shows proton spectra from white matter of anormal 9 year-old control and of Patients 2 and 3. Cerebral metabolites monitored include creatine (Cr), choline (Cho), myo-inositol (Ins), glucose (Glc.), N-acetylaspartate (NAA) and lactate (Lac) (8). The spectrum of Case 2 from severely affected white matter reveals the absence of NAA, Cr, Cho and Ins and a marked elevation of Lac and Glc. This spectrum is clearly different from anormal white matter spectrum and, apart from the lactate level similar to that ofcsf. Case 3 This girl is the child of healthy unrelated parents. Her older brother (born 1970) is weil. Apart from prophylactic antibiotic treatment during her first week of life her early development was uneventful. She was ahle to walk at 15 months (Fig. 4a), and spoke first words with 12 months. The parents noticed frequent respiratory infections. In May 1984 (2 years old) her gait became unsteady, buther spe~ch.remai~ednor~al. In August 1984 she was admitted to a pediatric hospital and Iffimobilized for 10 weeks. Thereafter she was unable to walke At 3 years crawling became difficult and at about 4.5 years she was unable to sit unsupported due to truncal ataxia. During the following years her muscle tone increased to severe spasticity. Between 6 and 7 years of age she lost her active language but re-

4 White Matter Disease: MRI and MRS Neuropediatrics 24 (1993) 247 Fig.4a Fig. 4 a and b Patient 3 aged 15 months (a) and 10 years (b). Fig.4b Fig.5a Fig. 5 a and b Fig.5b MRI of Patient 3 at the age of 10 years. T1-weighted coronal image (a), T2-weighted transverse image (b). mained mentally alert. In December 1988 she started having seizures and was put on anticonvulsive drugs. In spring 1990 visual problems became evident, but her hearing remained good. She suffered from recurrent respiratory infections and feeding was difficult. In 1992 (aged 10 years) she was referred for further investigations (Fig. 4b). She was in a poor nutritional state with anormal head circumference (53 cm). Her skin was pale, there was no organomegaly. She showed increased extensor tonus, generalized spasticity and dystonie movements most pronounced in her arms proving unable to use her hands or fingers. There was a mild horizontal nystagmus. Both optic disks were pale. Laboratory investigations excluded lysosomal, peroxisomal and mitochondrial disorders. There was no evidence for an amino or organic aciduria. Immunoglobulins were normal. CSF was normal including lactate. Nerve conduction velocity was within normal limits (N. peronaeus 63 m/s, N.

5 248 Neuropediatrics 24 (1993) suralis 58 mis). Acoustic evoked potentials were normal, visual evoked potentials were absent. The EEG showed a low voltage slow activity with a few isolated spikes and spike wave potentials. There was no photosensitivity. The most striking abnormality was seen on MRI (Fig. 5a, b). The white matter of both hemispheres showed a homogenous hypodensity with only few myelinated structures in the striatal area and cerebellum. The ventricles were enlarged, the corpus callosum small. MRS revealed an identical pattern to that observed in Case 2 (Fig. 3). The spectrum from affected white matter in this patient shows an almost complete loss ofnaa, Cr, Cho and Ins withincreased Lac and Glc. Discussion Our three children share some characteristics: their early development was normal. Between 2 and 3 years they developed ataxia and severe spasticity leading to almost total handicap within a few years. Bulbar symptoms and optic atrophy occurred late during their disease. They showed no signs of peripheral neuropathy. Mental functions, particulary alertness and acoustic responsiveness, are remarkedly wen preserved. There was no evidence for an infectious disease or one of the known lysosomal, mitochondrial or peroxisomal disorders. The most striking paraclinical findings were the unique white matter abnormalities best demonstrated by magnetic resonance imaging. Magnetic resonance spectra were different from all so far observed known white matter diseases. They were characterized by an almost complete absence of NAA, Cr, Cho and Ins. The clinical findings in these three children indicate a progressive disorder probably of autosomal recessive inhe.ritance. TheMRIand MRS investigationsrevealed uniform abnormalities so far not described in the literature. MRS investigations have until now only been performed in a few noninflammatory encephalopathies affecting the white matter (2, 5). Corresponding proton spectra are characterized by a pattern of decreased NAA and Cr and an increase of Cho, Ins and the occurrence of Lac in varying degrees. Spectra as observed in our three cases are very different. However, the metabolic abnormalities registered by MRS in neurometabolic disorders are stage-dependent and variable. Our patients were investigated at a latestagemanyyears aftertheonsetoftheir disease. MRS performed at an earlier stage ofthis disease mightprovide different results. NAA is taken as a marker of vital neuronal tissue, Cho and Ins are markers of glial-cellular activity and membrane-turnover. Phosphocreatine and lactate are thought F. Hanefeld et al to reflect cerebral energy metabolism. Although the results of MRS have to be judged with caution our observations would indicate an almost complete loss of vital neuronal tissue in white matter as weil as a poverty of glial cell elements and reduced membrane-turnover. Whether these can be interpreted as a sign of hypo- or demyelination remains open. The children described here resemble those mentioned by Sehiffinann and Barton (pers. communication). MRS in their four patients (all girls) showed a marked decrease of NAA, Cr and Cho in white matter, whereas Lac was not detected. A follow-up of their patients will probably show whether they belong to the same disease entity. Acknowledgments We are greatly indebted to Drs. Hamann and Lison, Hannover, and Drs. Munke and Zieh, Chemnitz, for referring these patients. References 1 Barkovich, A.]., G. Lyon, P. Evrard: Formation, maturation, and disorders ofwhite matter. AJNR 13 (1992) Bruhn, H., B. Kruse, G. C. Korenke, F Hanefeld, W Hänicke et al: Proton NMR spectroscopy of cerebral metabolie alterations in infantile peroxisomal disorders. J. Comput. Assist. Tomogr. 16 (1992) Frahm, ]., T Michaelis, K. D. Merboldt, H. Bruhn, M. L. Gyngell, W Hänicke: Improvements in localized IH-NMR spectroscopy of human brain. Water suppression, short echo times, and 1 ml resolution. J. Magn. Reson.90(1990) Frahm, ]., M. L. Gyngell, W Hänicke: Rapid scan techniques. In: D. D. Stark, W G. Bradley (Eds.): Magnetic resonance imaging. St. Louis, CV Mosby (1991) van der Knaap, M. 5.,]. van der Grond, P. R. Luyten et al: IH and 31p magnetic resonance spectroscopy of the brain in degenerative cerebral disorders. Ann. Neurol31 (1992) Kolodny, E. H.: Dysmyelinating and demyelinating conditions in infancy. Curr. Opinion Neurol. Neurosurg. 6 (1993) Kruse, B., F Hanefeld, H.]. Christen, H. Bruhn, T Michaelis et al: Alterations of brain metabolites in metachromatic leukodystrophy as detected by localized proton MR spectroscopy in vivo. Eur. J. Neurol. (in press) 8 Michaelis, T, K. D. Merboldt, W Hänicke, M. L. Gyngell, H. Bruhn,]. Frahm: On the identification ofcerebral metabolites in localized 1H-NMR spectra of human brain in vivo. NMR Biomed 4 (1991) Ogier, H.,]. Aicardi: Metabolie diseases. In: Aicardi,]. (Ed.): Diseases of the nervous system in childhood. Clinics in developmental medicine No. 115/118. London, Mac Keith Press (1992) Prof Dr. med. Dr. h.c. F. Hanefeld Abt. Kinderheilkunde Schwerpunkt Neuropädiatrie Georg-August-Universität Robert-Koch-Str. 40 D Göttingen Germany