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Alexander Disease: Diagnosis with MR Imaging

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Alexander Disease: Diagnosis with MR Imaging AJNR Am J Neuroradiol 22:541±552, March 2001 Alexander Disease: Diagnosis with MR Imaging Marjo S. van der Knaap, Sakkubai Naidu, Steven N. Breiter, Susan Blaser, Hans Stroink, Stephan Springer, Jacobus C. Begeer, Rudy van Coster, Peter G. Barth, Neil H. Thomas, Jacob Valk, and James M. Powers BACKGROUND AND PURPOSE: To date, the demonstration of Rosenthal ®bers on brain biopsy or autopsy specimens is considered a prerequisite for a de®nitive diagnosis of Alexander disease. We initiated a multiinstitutional survey of MR abnormalities in both presumed and con®rmed cases of Alexander disease to assess the possibility of an MR-based diagnosis. METHODS: MR imaging studies in three patients with an autopsy-based diagnosis of Al- exander disease were analyzed to de®ne MR criteria for the diagnosis. These criteria were then applied to 217 children with leukoencephalopathy of unknown origin. RESULTS: Five MR imaging criteria were de®ned: extensive cerebral white matter changes with frontal predominance, a periventricular rim with high signal on T1-weighted images and low signal on T2-weighted images, abnormalities of basal ganglia and thalami, brain stem abnormalities, and contrast enhancement of particular gray and white matter structures. Four of the ®ve criteria had to be met for an MR imaging-based diagnosis. In a retrospective analysis of the MR studies of the 217 patients, 19 were found who ful®lled these criteria. No other essentially new MR abnormalities were found in these patients. In four of the 19 patients, subsequent histologic con®rmation was obtained. The clinical symptomatology was the same in the patients with and without histologic con®rmation and correlated well with the MR abnormalities. MR abnormalities were in close agreement with the known histopathologic ®nd- ings of Alexander disease. CONCLUSION: The de®ned criteria are suf®cient for an in vivo MR imaging diagnosis of Alexander disease; only in atypical cases is a brain biopsy still necessary for a de®nitive diagnosis. Alexander disease is a rare, nonfamilial leukoen- disease by Alexander in 1949 (1), different clinical cephalopathy that typically presents with frontal subtypes have been recognized. Most of the re- preponderance of white matter abnormalities and ported cases have been the infantile variant, with macrencephaly. Since the ®rst description of this early onset of macrocephaly and rapid neurologic deterioration leading to early death (1±14). A neo- Received June 26, 2000; accepted after revision August 23. natal variant has been distinguished that is even From the Departments of Child Neurology (M.S.v.d.K.) and more rapidly fatal (15). A less frequently reported Radiology (J.V.), Free University Hospital, Amsterdam, the subtype is the juvenile variant, in which macro- Netherlands; the Department of Neurogenetics, Kennedy Krie- cephaly is a less consistent feature and onset of ger Institute, Baltimore, MD (S.N.); the Department of Radi- ology, Johns Hopkins Medical Institute, Baltimore, MD neurologic deterioration occurs later in childhood (S.N.B.); the Department of Neuroradiology, Hospital for Sick and is less rapid (16±21). Several instances of an Children, Toronto, Canada (S.B.); the Department of Child adult variant have also been described (19, 22±24). Neurology, St. Elisabeth Hospital, Tilburg, the Netherlands Laboratory investigations are not helpful in es- (H.S.); the Department of Pediatrics, Technical University, tablishing the diagnosis of Alexander disease. The Munich, Germany (S.S.); the Department of Child Neurology, hallmark of the disease is the presence of Rosenthal University Hospital, Groningen, the Netherlands (J.C.B.); the ®bers throughout the CNS. Rosenthal ®bers are ab- Department of Child Neurology, University Hospital, Gent, Belgium (R.v.C.); the Department of Child Neurology, Aca- normal intracytoplasmic proteinaceous inclusions demic Medical Center, Amsterdam, the Netherlands (P.G.B.); in ®brous astrocytes that have a distinctive hyaline the Department of Pediatric Neurology, Southampton General appearance under the light microscope (1±3) and a Hospital, Southampton, UK (N.H.T.); and the Departments of granular electron-dense quality under the electron Pathology and Neurology, University of Rochester Medical microscope (5, 19). Demonstration of Rosenthal ®- School, Rochester NY (J.M.P.). bers on histologic examination is considered a pre- Address reprint requests to M. S. van der Knaap, MD, De- partment of Child Neurology, Free University Hospital, P.O. requisite for a de®nitive diagnosis. There are ob- Box 7057, 1007 MB Amsterdam, the Netherlands. vious disadvantages associated with a diagnosis that is limited to histologic con®rmation. A brain q American Society of Neuroradiology biopsy, which is an invasive procedure, is a diag- 541 542 VAN DER KNAAP AJNR: 22, March 2001 nostic necessity, especially in cases of slow pro- TABLE 1: Clinical signs and symptoms in patients with a histo- gression. The only other option is to wait for post- logically con®rmed diagnosis mortem examination. MR imaging is known for its high sensitivity and Juvenile Infantile Variant Variant speci®city in identifying white matter disorders (25, 26). We initiated a multiinstitutional survey of No. of patients 2 1 MR imaging patterns in both presumed and con- Age at ®rst problems Birth to 6 wk ,2y ®rmed cases of Alexander disease to assess the pos- Delayed motor development Severe (2) Moderate Highest motor milestone None (2) Walking sibility of providing criteria for an MR imaging- Delayed mental development Severe (2) Mild based diagnosis. Behavioral problems 0 1 Epilepsy Severe (2) Mild (1) Feeding problems 2 1 Methods Vomiting 1 1 MR studies of three patients with a histopathologically con- Dif®culty swallowing/choking 2 1 ®rmed diagnosis of Alexander disease were available and Insuf®cient gain in weight 2 1 formed the basis of the de®ned MR imaging criteria. These Speech problems Not applicable 1 criteria were then applied to 217 children with leukoencepha- Macrocephaly 2 0 lopathy of unknown origin whose MR studies we had received Poor eye contact 2 0 for review. In these patients, well-known causes of childhood Hypotonia Generalized (1) 0 leukoencephalopathy had been excluded by means of the fol- axial (1) lowing laboratory examinations: urine organic acids, including Hypertonia of the limbs 1 1 N-acetyl aspartate; plasma amino acids; serum lactate and py- Hyperre¯exia 2 1 ruvate; very long-chain fatty acids; and arylsulfatase A, gal- Cerebellar ataxia Not testable 1 actocerebrosidase, b-galactosidase, and b-hexosaminidase ac- Extrapyramidal signs 0 1 tivity. Patients who ful®lled the MR imaging criteria were Deterioration Rapid Slow selected for further evaluation. Age at death 10 and 11½ mo, 10 y All MR studies were examined retrospectively using a list respectively of many anatomic white and gray matter structures (27), which were scored as either normal or abnormal. In addition, other Note.ÐNumbers indicate the number of patients in whom a partic- characteristics were scored (27), including swelling and atro- ular feature was observed. phy of white and gray matter structures, presence of cysts, and contrast enhancement. The criterion for swelling of cerebral white matter was volume increase with broadening of the gyri. The criterion for swelling of the basal ganglia and thalamus in infancy. Onset of neurologic deterioration was was volume increase with compression of the ventricles. The delayed and gradual. Signs of bulbar dysfunction criterion for atrophy was volume decrease with widening of became prominent, including speech problems, the ventricles and subarachnoid spaces. By comparing the im- bouts of vomiting, and progressive swallowing dif- ages of the patients, we determined the relative severity of ®culties, eventually necessitating tube feeding. characteristics, such as swelling, atrophy, signal change, and Spasticity and cerebellar ataxia arose late in the contrast enhancement, and distinguished two grades: 1) clearly present, and 2) slight to mild. In the analysis, we divided the course of the disease, and the patient remained MR studies into early and late, based on whether they were normocephalic. obtained before or soon after the onset of neurologic deterio- Two MR studies were obtained in the two pa- ration or late in the course of the disease. All images were tients with infantile Alexander disease, in one pa- reviewed independently by two investigators, and consensus tient at an early stage and in the other patient at a was reached when there was a disagreement between their late stage of the disease (Table 2). The early MR interpretations. The medical histories and clinical ®ndings were document- study (Fig 1) showed that the frontal white matter ed, including onset of clinical symptoms and disease course, had a slightly higher signal intensity than normal presence of mental and motor problems, signs of bulbar dys- unmyelinated white matter on T2-weighted images function, epilepsy, head circumference, height, and weight. and slightly lower signal intensity on T1-weighted images. Other ®ndings included signal abnormality and some swelling of the basal ganglia, a periven- Results tricular rim of low signal intensity on T2-weighted images and high signal intensity on T1-weighted Patients with a Histologically Con®rmed images, and areas of signal abnormality in the brain Diagnosis of Alexander Disease stem, including the medulla and the entire area of Of the three patients with an autopsy-con®rmed the midbrain, except
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