Brain magnetic resonance imaging in 23 patients with mucopolysaccharidoses and the effect of bone marrow transplantation.код для вставкиСкачать
Brain Magnetic Resonance Imaging in 23 Patients with Mucopolysaccharidoses and the Effect of Bone Marrow Transplantation Toshiyuki Seto, MD,1 Kinuko Kono, MD,2 Kyoko Morimoto, MD,1 Yuichi Inoue, MD,2 Haruo Shintaku, MD,1 Hideji Hattori, MD,1 Osamu Matsuoka, MD,1 Tsunekazu Yamano, MD,1 and Akemi Tanaka, MD1 A longitudinal study of cranial magnetic resonance imaging (MRI) was carried out in 23 patients with mucopolysaccharidoses (MPS); 1 each of types IH, VI, and VII; 2 of type IS; 10 of type II; and 4 each of types IIIB and IVA. Six types of distinct abnormalities were 1) cribriform changes or spotty changes in the corpus callosum, basal ganglia, and white matter; 2) high-intensity signal in the white matter on T2-weighted image; 3) ventriculomegaly; 4) diffuse cerebral cortical atrophy; 5) spinal cord compression; and 6) megacisterna magna. The cribriform changes that corresponded to dilated perivascular spaces were found in the patients with MPS IS, II, and VI. The patchy and diffuse intensity changes were found in the patient with MPS II and IIIB, respectively. MPS IH and the severe type of MPS II showed marked ventriculomegaly. Marked cerebral atrophy was observed in all MPS IIIB patients and in the severe type of MPS II patients. Spinal cord compression was a feature usually observed in MPS IH, IVA, VI, and VII. Megacisterna magna was frequent in the patients with MPS II (6/10). In two of five patients, the therapeutic effect of bone marrow transplantation (BMT) was remarkable. Both the cribriform changes and the intensity change of the white matter in a MPS VI patient disappeared eight years after the BMT. Slight improvement of cribriform change was noted in one patient with MPS II three years after the BMT. MRS was not sufficient to estimate the accumulation of glycosaminoglycans but was useful for evaluating neuronal damages. Ann Neurol 2001;50:79 –92 The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of enzymes catalyzing the stepwise degradation of gycosaminoglycans (GAG; mucopolysaccharides). Depending on the enzyme deficiency, the catabolism of dermatan sulfate, heparan sulfate, or keratan sulfate is blocked, singly or in combination; chondroitin sulfate may also be involved. There are 10 known enzyme deficiencies that give rise to six distinct MPS.1 The accumulation of GAG with the enzyme deficiencies causes the systemic diseases in variable degrees, including diseases of the central nervous system (CNS). Mental retardation is characteristic of MPS IH (Hurler syndrome), the severe forms of MPS II (Hunter syndrome) and VII (Sly syndrome), and all subtypes of MPS III (Sanfilippo syndrome), but normal intellect may be retained in other MPS. The mechanism of CNS dysfunction in MPS is not well understood. The deficiency of ␣-L-iduronidase activity causes three major clinical phenotypes, MPS IH, IH/S (Hurler-Scheie syndrome), and IS (Scheie syndrome). MPS IH is the most severe form, MPS IS is the mildest form, and MPS IH/S represents an intermediate phenotype. MPS IH shows mental retardation, whereas MPS IS does not. The difference in clinical severity, including the mental retardation, is attributed to the residual activity of the deficient enzyme resulting from the molecular abnormalities. In the case of MPS II, iduronate sulfatase deficiency, which shows a wide range of clinical involvement from severe to mild, the same relationship between the clinical phenotype and the enzyme dysfunction can be noted. The severe forms of both enzyme deficiencies, ␣-L-iduronidase deficiency and iduronate sulfatase deficiency, usually show mental retardation. It is suggested that a small amount of enzyme activity can spare the CNS. In MPS III, there are four biochemically diverse groups, type A (heparan N-sulfatase deficiency), type B (␣-N-acetylglucosaminidase deficiency), type C (acetyl-CoA: ␣-glucosamine acetyl- From the Departments of 1Pediatrics and 2Radiology, Osaka City University Graduate School of Medicine, Osaka, Japan. Address correspondence to Dr Tanaka, Department of Pediatrics, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. E-mail: firstname.lastname@example.org Received Sep 5 , 2000, and in revised form Dec 11. Accepted for publication Feb 13, 2001. Published online 5 May 2001. © 2001 Wiley-Liss, Inc. 79 Table. Patient Characteristics Patient No. Diagnosis Age(s) at MRI (Years) Age at BMT (Years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 IH IS IS II Severe II Severe II Intermediate II Intermediate II Intermediate II Mild II Mild II Mild II Mild II Mild IIIB IIIB IIIB IIIB IVA IVA IVA IVA VI VII 7 21,31 5,13,14,15,17 4,7 5,9,10,12,13,15,16,18 12 4 2 8,10,12,13,15,16 6,10,12,14,15 5,6,7,8 10,18 8,16 5,12,15 7,8,9,15 10,19 4,5,6 18 13 4 12 11,15,17,21,22,25 11,13,15,17 — — — — — — — 2 9 — 6 — — — — — — — — — 15 13 — transferase deficiency), and type D (Nacetylglucosamine 6-sulfatase deficiency); however, all patients with MPS III show a similar clinical phenotype, with profound mental deterioration and mild somatic manifestations. Previously, we and others reported that magnetic resonance imaging (MRI) of the brain in MPS was often abnormal. However, these previous studies were limited to only MPS IS, II, III, and VI.2– 6 In this study, we report MRI findings of 23 patients with various types of MPS, including follow-up studies of eight patients who were reported previously2 and patients who received bone marrow transplantation (BMT).7 Our study emphasizes the importance of MRI contribution for the evaluation of the progression of disease processes and of the effectiveness of therapeutic intervention. We also investigated the possible usefulness of magnetic resonance spectroscopy (MRS) for evaluation of the extent of neuronal degeneration and accumulation of GAG. Patients and Methods Twenty-three patients with MPS were studied. The diagnosis was made from the enzyme analysis in all patients. Diagnosis of individual patients and ages when MRI studies were conducted are summarized in the Table. Molecular diagnosis was also carried out in patients 1, 5, 10, 11, 14 –19, and 23. Because the patients with MPS II show very different clinical phenotypes, we classified them into severe (patients 4 and 5), 80 Annals of Neurology Vol 50 No 1 July 2001 Group I Mental Retardation at the Latest MRI Basal Ganglia White Matter Corpus Callosum 2 0 0 3 3 1 1 0 0 0 0 0 0 3 3 3 3 0 0 0 0 0 0 0 0 0 2 033 2 0 0 1 0 130 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 133 2 1 1 0 0 331 0 0 0 0 0 0 0 0 0 0 231 0 0 0 132 2 133 2 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 intermediate (patients 6 – 8), and mild (patients 9 –13) groups according to the severity of mental retardation. Patients 8, 9, 11, 21, and 22 received BMT. Brief clinical summaries, mainly of neurological involvement in individual patients, are listed below. Patient 1 (MPS IH): Seven-year-old female. A ventricularperitoneal shunt was placed for the treatment of communicating hydrocephalus at age 1 year. Her intellect has deteriorated progressively since 4 years of age. Patient 2 (MPS IS): Thirty-five-year-old male. Visual impairment was detected at age 10 years and diagnosed as MPS IS. His intellect was normal. Patient 3 (MPS IS): Nineteen-year-old female. She was diagnosed by the urinary MPS screening test at age 4 years. She had normal intellect. She has had migrainelike attacks since age 10 years. Patient 4 (MPS II severe): Eight-year-old male. He could say only a few words and understand a few sentences at 6 years of age. Patient 5 (MPS II severe): Eighteen-year-old male. He was diagnosed at 1.5 years old. He deteriorated progressively. He has been apathetic without saying any words since 13 years of age. Patient 6 (MPS II intermediate): Eighteen-year-old male. His mentality was borderline normal at 12 years of age. Patients 7 and 8 (MPS II intermediate): Siblings; 4-year-old and 2-year-old males. The elder brother had speech retardation at age 3 years. The younger brother received BMT at age 2 years. Patient 9 (MPS II mild): Nineteen-year-old male. He was Table. Continued Group II Group IV Patchy Diffuse Group III Interhemispheric Sylvian Group V Group VI MRS (NAA/Cr) (Age Examined, Years) 2 0 0 2 0 2 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 3 1 0 1 0 2 1 1 1 0 0 0 0 0 0 2 1 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 1 3 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 0 1 1 1 0 0 1 031 1 0 1 1 1 0 0 0 0 0 0 1 0 0 0 0 0 0 Not done Not done Not done 1 (5) Not done Not done Not done 0 (2) 0 (15) Not done 0 (7) Not done Not done Not done 1 (15) Not done 1 (5) Not done Not done Not done Not done 0 (23) 0 (16) 32 31 31 30 31 33 33 31 3 3 3 3 3 3 3 3 32 33 3 3 3 3 3 3 3 2 treated with BMT at age 9 years. Somatic involvement except for the skeletal deformities gradually improved after the transplantation. His intellect remained normal. Patient 10 (MPS II mild): Fifteen-year-old male. Joint stiffness was noted at the age of 5 years, and the diagnosis as MPS II was made. Patient 11 (MPS II mild): Eight-year-old male. He received BMT when he was 5 years old. Somatic involvement improved quickly, and his intellect has been fairly good. Patients 12 and 13 (MPS II mild): Siblings; 20-year-old and 18-year-old males. They showed minimal somatic involvement and fairly good intellect. Patients 14 and 15 (MPS III B): Siblings; 18-year-old male and 16-year-old female. The brother had delay of speech development and uncontrollable hyperactivity at age 3 years. He developed a rapid mental deterioration and a progressive dementia. He has been suffering from epileptic attacks since 10 years of age. He did not have any contact with the environment, nor could he stand by himself at age 12 years. The sister showed behavior problems at age 5 years. She showed milder progression than her brother. Patient 16 (MPS III B): Twenty-four-year-old male. Developmental delay was noted at age 2 years. He had epileptic attacks when he was 12 years of age. He was bedridden at age 15 years. He began to receive nasal tube feeding at age 19 years. Patient 17 (MPS III B): Six-year-old male. He showed the most rapid deterioration among these 4 MPS IIIB patients. He could not say any words at age 5 years and could not walk at age 6 years. Patient 18 (MPS IV A): Twenty-three-year-old female. Bone 32 33 33 33 33 deformities were noted at age 1 year. She became quadriplegic when she had overflexion of the neck at age 9 years. Her intellect was fairly good, although she was bedridden. Patient 19 (MPS IV A): Fourteen-year-old male. He had normal intellect and decreased deep tendon reflexes. Patient 20 (MPS IV A): Five-year-old female. She had normal intellect and increased deep tendon reflexes at age 4 years. Patient 21 (MPS IV A): Fifteen-year-old male. He had very mild bone deformities, and he received BMT at age 15 years. Patient 22 (MPS VI): Twenty-five-year-old female. She received corneal transplantation at age 12 years and BMT at age 13 years. The hepatomegaly has improved, and the cardiac and the skeletal involvement has not progressed since the BMT. She had a fairly good intellect. Patient 23 (MPS VII): Seventeen-year-old female. She was a patient with the mild form of MPS VII and showed clinical features similar to those of MPS IV.8 MRI Examination The studies were performed at 1.5 Tesla on two different systems, spin echo T1-weighted and fast spin echo T2weighted, each including axial, coronal, and sagittal acquisitions. Repetition time (TR), echo time (TE), and the slice thickness in T1-weighted echo were 500 – 670 msec, 10 –17 msec, and 5 mm, respectively. In T2-weighted fast spin echo, TR, TE, and the slice thicknesses were 4,000 – 6,000 msec, 90 –105 msec, and 5 mm, respectively. Fluid low-attenuation inversion recovery (FLAIR) was also studied in patients 1, 11, 15, 17, 22, and 23. Seto et al: MRI in Mucopolysaccharidoses 81 Evaluation of the Lesions in MRI The six types of lesions (groups I–VI) were graded by the scoring method according to a previous report,3 with some modifications. The cystic or cribriform lesions (group I) were graded in T1-weighted images as follows: 0 ⫽ none; 1 ⫽ mild, 10 or fewer small (⬍3 mm) cystic lesions; 2 ⫽ moderate, greater than 10 small cystic lesions; and 3 ⫽ severe, many small and large (ⱖ3 mm) cysts. The lesions were graded for each area of basal ganglia, white matter, and corpus callosum. The white matter signal changes (group II) observed in T2-weighted image were divided into two types. One was patchy lesions that appeared mainly at periventricular area, and the other was diffuse lesions affecting the entire cerebral white matter. The patchy lesions were graded as follows: 0 ⫽ none; 1 ⫽ mild, a few limited in the periventricular area; and 2 ⫽ severe, in most parts of periventricular area and other white matter areas. The diffuse lesions were judged to be 0 ⫽ none or 1 ⫽ existing. The ventricular enlargement (group III) was graded as follows: 0 ⫽ none; 1 ⫽ mild, ⬍3 mm widening of the third ventricle, without temporal horn dilatation; 2 ⫽ moderate, ⬎5 mm and ⬍1 cm widening of the ventricles; and 3 ⫽ severe, ⬎1 cm dilatation of the third ventricle, with bulbous configuration. The brain atrophy (group IV) was graded as follows: 0 ⫽ none; 1 ⫽ mild, mild widening of the Sylvian and interhemispheric fissures by ⬍3 mm, but not all of the sulci involved; 2 ⫽ moderate, widening of all fissures and sulci from 3 to 5 mm; and 3 ⫽ severe, widening of all fissures and sulci by ⬎5 mm with definite loss of cortex and white matter. The compression of the spinal cord at craniocervical junction (group V) was evaluated by the percentage of reduction in the midsagittal diameter of the spinal cord. The severity of the compression was graded as follows: 0 ⫽ none; 1 ⫽ mild, reduction ratio ⬍50%; and 2 ⫽ severe, reduction ratio ⱖ50%. Megacisterna magna (group VI) was judged to be 0 ⫽ none or 1 ⫽ exsisting. Mental retardation was graded as follows: 0 ⫽ none, normal mentality; 1 ⫽ borderline, mildly retarded, IQ/DQ 40 – 60; 2 ⫽ moderately retarded, IQ/DQ ⬍40; 3 ⫽ severely retarded, IQ/DQ not measurable. 1 H-MRS Examination 1 H-MRS was performed on a 1.5 Tesla MR system with a circularly polarized head coil on 2 ⫻ 2 ⫻ 2 cm3 volume of interest. Each volume of interest was confined to white matter of the frontal and the occipital lobes and the basal ganglia in patients 4, 8, 9, 11, 15, 17, 22, and 23. The spectra were obtained using spin echo with 1,500 msec of repetition time and 30 msec of echo time. The ratio of the resonance peak of N-acetylaspartic acid (NAA) to that of creatine plus phophocreatine (Cr) was analyzed for each spectrum.9 –11 The value of NAA/Cr was recorded as normal (score 0) and decreased (score 1) for age. To analyze the spectrum of the accumulated GAG in the brain, an experimental study for chemical material was carried out. A 50 ml Falcon tube was filled with 1% chondroitin sulfate A/C (Sigma, St. Louis, MO) in water and packed in agar capsule (16 cm in diameter; see Fig 9A). The 82 Annals of Neurology Vol 50 No 1 July 2001 volume of 2 ⫻ 2 ⫻ 2 cm3 in the chondroitin sulfate A/C solution was analyzed. BMT Patients 8, 9, and 11 with MPS II; patient 21 with MPS IVA; and patient 22 with MPS VI received BMT from their HLA-matched siblings at the ages of 2, 9, 6, 15, and 13 years, respectively. The donors were noncarriers with normal enzyme activity for patients 8, 11, and 22 and heterozygous carriers for patients 9 and 21. Results The MRI findings, MRS, and degree of mental retardation for each patient are summarized in the Table by the scores described for the patients and methods. Findings for individual patients are briefly summarized below. Patient 1 (MPS IH): Many patchy lesions of high intensity signal were found at periventricular and other areas of the white matter in T1- and T2weighted images (Fig 1A,B), and no cribriform change was noted. Severe enlargement of the lateral ventricles was observed. Patient 2 (MPS IS): Slight dilatation of ventricles was present on axial and coronal sections at age 21 years. No significant change was observed at age 31 years. Patient 3 (MPS IS): Several cystic lesions were found in the corpus callosum on the T1-weighted image at the ages of 15 and 17 years. Patient 4 (MPS II severe): At the age of 4 years, ventricular dilatation and mild cortical atrophy were observed. There were many small cystic lesions in every part of the white matter and several large lesions in the periventricular region of the anterior horn (Fig 2A,B). Some of these cribriform changes appeared to be linear and parallel to the blood vessels. The intensity of the white matter was increased in the T2-weighted image, in the periventricular region of the posterior horn, and in other areas (see Fig 2B). The cisterna magna was markedly enlarged. Patient 5 (MPS II severe): Cribriform changes were already present at age 5 years. White matter signal changes and brain atrophy appeared at age 9 years. At age 15 years, the cerebrum was atrophied, with enlarged lateral ventricles, whereas the midbrain, the fourth ventricle, and the cerebellum appeared normal, suggesting normal cerebrospinal fluid pressure. Cribriform changes were found in many parts of the brain, especially in the corpus callosum, basal ganglia, and periventricular regions both in T1- and in T2-weighted images (Fig 3A– C). Patchy lesions with high intensity at deep white matter in T2-weighted image (see Fig 3C) Fig 1. T1 (A)- and T2 (B)-weighted images of axial view in patient 1 [mucopolysaccharidosis (MPS) IH] at the age of 7 years. Intensity changes of the periventricular area and severe enlargement of the lateral ventricle were present. and large cisterna magna in sagittal view (see Fig 3B) were found. Patient 6 (MPS II intermediate): Mild brain atrophy and cribriform changes in every part of the white matter were present at age 12 years. In the T2weighted image, increased intensity of the white matter including the brainstem was observed. Patients 7 and 8 (MPS II intermediate): In both patients, cribriform lesions were found in the white matter and corpus callosum. The brains were not atrophic. Patient 9 (MPS II mild): A mild ventricular dilatation, enlargement of perivascular spaces at basal ganglia, and patchy intensity changes in the periventricular white matter were present at the age of 8 years (Fig 4A,B). No significant change was found at age 16 years, 7 years after the BMT (see Fig 4C,D). Patient 10 (MPS II mild): No abnormality was found except for the empty sella and megacisterna magna at the ages of 6, 10, 12, and 14 years. Mild ventricular dilatation and small patchy intensity changes of the white matter were observed at age 16 years. Patient 11 (MPS II mild): Multiple spotty or linear lesions in the parietal and occipital lobes and highintensity areas in the deep white matter around the posterior horns were observed when he was 5 years old (Fig 5A,B). These lesions had slightly diminished in size at the age of 8 years (see Fig 5C,D), 2.5 years after the BMT. Patients 12 and 13 (MPS II mild): In both patients, the brain MRI were normal at ages 18 and 16 years, respectively. Patients 14 and 15 (MPS IIIB): Severe brain atrophy, subdural fluid collection, and a thick skull were observed in patient 14 at age 15 years (Fig 6A). The increased intensity of the white matter was present diffusely in all parts of the cerebrum (see Fig 6B), but the brainstem and the cerebellum appeared normal. Neither the perivascular space enlargement nor the cribriform changes was observed. In patient 15, at the age of 15 years, severe brain atrophy and subdural fluid collection were found, but these changes were milder than those in patient 14. The finding of the increased intensity of the white matter was limited to the parietal, temporal, and occipital lobes. Patient 16 (MPS IIIB): Brain atrophy and abnormal intensity of the white matter were observed at age 10 years. At age 19 years, progression of the brain atrophy was evident. Patient 17 (MPS IIIB): Brain atrophy and large cisterna magna were found. T2-weighted image and FLAIR image showed increased intensity of the white matter. The intensity change was diffuse Seto et al: MRI in Mucopolysaccharidoses 83 Fig 2. T1 (A)- and T2 (B)-weighted images in patient 4 [mucopolysaccharidosis (MPS) II, severe] at the age of 4 years. Brain atrophy, ventricular dilatation, white matter signal changes, and cribriform changes were present. rather than patchy. The brain atrophy progressed very rapidly. Patient 18 (MPS IVA): The brain image was normal, although severe spinal cord compression at level C1/2 was present at age 19 years. Patient 19 (MPS IVA): The spinal cord compression at level C1/2 was found at age 13 years. Patient 20 (MPS IVA): The spinal cord compression at level C1/2 was observed, and the remainder of the CNS was normal when she was 4 years old (Fig 7). Patient 21 (MPS IVA): No pathological findings were seen either in the brain or in the spinal cord. Patient 22 (MPS VI): She had many spotty lesions close to both lateral ventricles and some patchy le- Fig 3. T1 (A,B)- and T2 (C)-weighted images in patient 5 [mucopolysaccharidosis (MPS) II, severe] at the age of 15 years. Large cystic lesions were found in basal ganglia (A) and corpus callosum (B). Medium-sized cysts and intensity changes of white matter are shown in C. Large cisterna magna is shown in B. 84 Annals of Neurology Vol 50 No 1 July 2001 Fig 4. T1 (A,C)- and T2 (B,D)-weighted images in patient 9 [mucopolysaccharidosis (MPS) II, mild] at the ages of 8 [before bone marrow transplantation (BMT); A,B] and 16 (7 years after BMT; C,D) years. Patchy intensity changes and mild ventricular dilatation were present before the BMT (A,B), which had not changed 7 years after the BMT (C,D). Seto et al: MRI in Mucopolysaccharidoses 85 Fig 5. T1 (A,C)- and T2 (B,D)-weighted images in patient 11 [mucopolysaccharidosis (MPS), mild] at the ages of 5 [before bone marrow transplantation (BMT); A,B] and 8 (2.5 years after BMT; C,D) years. Cysts of various sizes were present in the white matter of posterior lobes before the BMT (A,B), which were slightly diminished 3 years after the BMT (C,D). 86 Annals of Neurology Vol 50 No 1 July 2001 Fig 6. T1 (A)- and T2 (B)-weighted images in patient 14 [mucopolysaccharidosis (MPS) IIIB] at the age of 15 years. Severe brain atrophy, thick skull, and diffuse intensity change of the white matter were observed. sions before the BMT (Fig 8A,B). The patchy lesions and the spotty lesions began to diminish 2 years after the BMT. The patchy lesions disappeared, and the cribriform changes were signifiFig 7. Sagittal view of T2-weighted image in patient 20 [mucopolysaccharidosis (MPS) IV A] at the age of 4 years. Compression of the spinal cord by the soft tissue at level C1/2 is shown. cantly diminished when she was 21 years old, 8 years after the BMT (see Fig 8C,D). The spinal cord compression did not improve with the BMT. Patient 23 (MPS VII): The spinal cord compression at level C1/2, similar to the finding of the patient with MPS IVA, was present. Her brain image was completely normal. Six types of changes were distinguished as follows. Group I; cribriform changes or spotty lesions: These are considered to be the result of the abnormal enlargement of perivascular spaces. Here the mucopolysaccharide-loaded foamy cells accumulated. They were found in the corpus callosum (see Fig 3B), basal ganglia (see Fig 3A), and white matter (see Figs 5A, 8A). The changes appeared most frequently and severely in the patients with MPS II. They were also found in the patients with MPS I and VI. The degree of the changes was almost parallel to the severity of the disease, although they were seen in patients not only with but also without mental retardation. Some lesions improved after the BMT in patients 11 (see Fig 5) and 22 (see Fig 8). The NAA/Cr value by MRS of the area with spotty lesions in patient 11 was normal (data not shown). Seto et al: MRI in Mucopolysaccharidoses 87 Fig 8. T1 (A,C)- and T2 (B,D)-weighted images in patient 22 [mucopolysaccharidosis (MPS) VI] at the ages of 11 years [before bone marrow transplantation (BMT); A,B] and 21 (8 years after BMT; C,D) years. Cystic lesions were dramatically diminished, and patchy intensity changes disappeared completely after the BMT. 88 Annals of Neurology Vol 50 No 1 July 2001 Seto et al: MRI in Mucopolysaccharidoses 89 Group II; white matter signal changes: These were suggested to be gliosis in the white matter or demyelination. They usually appeared in periventricular white matter and sometimes in subcortical regions or other parts of white matter in T2-weighted images. They were seen in the patients with MPS I (see Fig 1), II (see Figs 2B, 3C, 4B), and VI (see Fig 8B) as patchy lesions. In patient 22, the patchy lesions were diminished after the BMT. The intensity changes appeared diffusely in the entire white matter in the patients with MPS IIIB (see Fig 6B), different from those in other types of MPS patients. The NAA/Cr values by MRS of the area with diffuse high intensity in two patients with MPS IIIB (patients 5 and 17; Fig 9C,D) were significantly decreased, which suggested loss of neurons. Group III, ventricular enlargement: This was found in the patients with MPS IH (see Fig 1) and II (see Figs 2– 4) as the result of the insufficient absorption of the cerebrospinal fluid or brain atrophy in the patients with MPS IIIB (see Fig 6). Group IV, brain atrophy: This usually meant general damage of the brain and was found in the patients with mental retardation. The brain atrophy appeared in all of the MPS IIIB patients (see Fig 6) and in the patients with the severe type of MPS II (see Figs 2, 3). Group V, Spinal cord compression: This was caused by thickening of the soft tissue or dura mater around the dens. It was usually seen in the patients with severe dysmorphic bone changes, such as in the patients with MPS IH, IVA (see Fig 7), VI, and VII. Group VI, megacisterna magna: This was found very frequently in the patients with MPS II (6/10; Fig 3B). MRS Findings Significant decreases of the NAA/Cr ratio for age9 –11 were shown in patients 4, 15, and 17 (Fig 9C,D), who have mental retardation, but it was in normal ranges in patients 8, 9, 11, 22 (see Fig 9E,F), and 23, who have normal intellect. The peak of GAG was seen around 3.7 ppm in the chemical standard analysis (see Fig 9A,B). Among these patients, the peak around 3.7 ppm was larger in patient Š 17 (see Fig 9D) than in patient 22 (see Fig 9F), which might reflect the difference in the amount of accumulated GAG. Effect of BMT Patient 9, who received BMT at the age of 9 years from his heterozygote sister, had cribriform changes in corpus callosum, mild ventricular enlargement, and patchy intensity changes in periventricular white matter before the BMT (see Fig 4A,B). None of them improved at 7 years after the therapy (see Fig 4C,D), but his intelligence has remained normal. Patient 11 received BMT from his healthy brother when he was 6 years old. His brain MRI before the treatment showed multiple cystic lesions in basal ganlia and the white matter (see Fig 5A,B). These lesions appeared slightly diminished when he was 8 years old, 2.5 years after the BMT (see Fig 5C,D). Patient 22 received BMT from her noncarrier brother when she was 13 years old. Her brain MRI at the age of 11 years showed patchy intensity changes in the white matter and many lesions of cribrriform changes (see Fig 8A,B). Both the intensity changes and the cribriform changes were definitely diminished by age 15 years. By the age of 21 years, the intensity changes disappeared completely, and the cribriform changes diminished dramatically (see Fig 8C,D). It was difficult to evaluate the effect of BMT for patients 8 and 21 because of the short follow-up period of less than 1 year. Discussion The neurological involvements of mucopolysacchridoses are well-known clinically. In patients with MPS types I, II, or VII, only the severe forms show mental retardation. The patients deteriorate progressively, but they look calm and dull compared to the patients with MPS III. MPS III is characterized by severe CNS degeneration. Presenting neurological features can include hyperactivity with aggressive behavior, delayed development, and sleep disorders. In patients with MPS IV or VI, CNS is not involved, but some patients show cervical myelopathy resulting from the spinal cord compression. We carried out the MRI and MRS studies of the CNS for the 23 patients with various types of MPS Fig 9. (Overleaf) (A,B) Experimental study of magnetic resonance spectroscopy (MRS) for a chemical standard solution of gycosaminoglycans (GAG; chondroitin sulfate A/C). (A) A 50 ml screw-cap tube (Falcon) was filled with 1% chondroitin sulfate A/C (Sigma) in water and put in an agar capsule (16 cm in diameter). The square shows the cube of the analyzed volume. (B) The spectrum of chondroitin sulfate A/C. It was shown by a broad peak at around 3.7 ppm. (C,D) MRS in patient 17 at the age of 5 years. The spectrum was acquired from the right frontal lobe as shown in C. The peak of N-acetylaspartic acid (NAA) was small, and NAA/creatine plus phophocreatine (Cr) ratio was low for age. There was a broad peak around 3.7 ppm, but it was difficult to estimate the amount of accumulated GAG. (E,F) MRS in patient 22 at the age of 23 years. The spectrum was acquired from the same area as in patient 17, as shown in E. The spectrum and the ratio of NAA/Cr were normal for age. 90 Annals of Neurology Vol 50 No 1 July 2001 and summarized the features of MRI and the clinical CNS involvement. Changes in groups I and II are the direct consequences of the accumulation of GAG in CNS. The changes in group I (cribriform changes) were found in the patients with MPS I, II, and VI. They were shown in the patients with both normal and abnormal intellect, which suggested that they do not affect the neurons but occupied the perivascular spaces by accumulated substances. This is consistent with the result of NAA/Cr by MRS analysis in patient 11. In microscopic studies, the enlarged perivascular spaces appeared collagenous or glial trabeculae, and collection of foamy cells was observed.12–14 Group II changes (white matter signal changes) were found in a patient with type IH, some patients with type II, all the patients with type IIIB, and a patient with type VI. The lesions are speculated to be demyelination, gliosis, or accumulation of foamy cells.12,14 –16 These intensity changes appeared diffusely in MPS IIIB and patchily in other types of MPS. In patient 22, the disappearance of the patchy lesions of group II after the BMT is noteworthy (see Fig 8), and the cribriform changes (group I) were also diminished. However, no significant change was observed in patient 9 (see Fig 4). There would be a difference in the nature of the enzyme proteins or in the accumulated materials between MPS II and MPS VI.17,18 However, in patient 11, with MPS II, some effect of BMT was shown (see Fig 5). The cause of the difference in the effect between these two MPS II patients might be the different subtypes of MPS II or the difference in the donor states between carrier and noncarrier. MPS II is particularly important in Japan because of the high incidence, accounting for 54% of all MPS patients by the analysis of the registered members of the Japanese Society of the Families and the Patients with MPS. It is important to recognize which of the patients with MPS II would have a severe form or a mild form in the early stage for the indication of BMT or genetic counseling. The MRI findings might be of some help in predicting the future mental state of these patients. MPS III is quite different from other types of MPS. The brain does not have any changes of group I, but the MRI showed diffusely increased intensity of the white matter (group II) and severe brain atrophy (group IV). Neurons might be directly damaged in the patients with MPS III.16,19 Thus, the diffuse intensity change would mean neuronal loss, which was consistent with the decreased ratio of NAA/Cr by MRS analysis in patients 15 and 17. On the other hand, the patchy intensity changes that appeared in other types of MPS would not mean the neuronal degeneration but the accumulation of foamy cells. Lee et al.3 reported that cribriform changes existed in the patients with type IIIA, although, in our patients with type IIIB, those changes did not exist at all. The changes of groups III, V, and VI are the results of the GAG accumulation in peripheral tissue of CNS. Communicating hydrocephalus (group III), caused by the insufficient absorption of cerebrospinal fluid, was found in a patient with MPS IH12,15,20 and in some patients with MPS II. Compression of the spinal cord (group V) was characteristic in MPS IV. This was caused not by the odontoid dysplasia or by the subluxation but by the thickening of the soft tissue or dura mater around the dens.21–23 Similar change was observed in the patients with MPS VI and VII. Megacisterna magna (group VI) was found very frequently in the patients with MPS II. Lee et al.3 reported previously the inverse relationship between the degree of cribriform changes (group I) and the degrees of white matter changes, ventricular enlargement, and atrophy (groups II, III, and IV). However, in our study, each group of abnormal findings became more severe with the disease progression. The MRS analysis would be useful for the follow-up of progressive patients or BMT-treated patients. Whereas NAA is an amino acid specifically located in neurons, the decreasing of NAA/Cr means the neuronal damages or loss of neurons, causing the mental deterioration.9 –11 Our results showing that NAA/Cr was decreased in the patients with mental retardation are consistent with the fact. 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