DOI: 10.1148/rg.253045118
RadioGraphics 2005;25:619-631
© RSNA, 2005
Childhood X-linked Adrenoleukodystrophy: Clinical-Pathologic Overview and MR Imaging Manifestations at Initial Evaluation and Follow-up1
Ji Hyung Kim, MD and
Hyon J. Kim, MD
1 From the Department of Diagnostic Radiology, Konyang University Hospital, 685 Gasuwon-dong, Seo-gu, Daejeon City 302–718, South Korea (J.H.K.); and the Department of Pediatrics, Genetic Clinics, Ajou University Hospital, Suwon, South Korea (H.J.K.). Presented as an education exhibit at the 2003 RSNA Scientific Assembly. Received May 21, 2004; revision requested September 10 and received January 3, 2005; accepted January 5. All authors have no financial relationships to disclose.
Address correspondence to J.H.K. (e-mail: radol{at}unitel.co.kr).
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Abstract
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X-linked adrenoleukodystrophy (ALD) is a rare metabolic disorder caused by peroxisomal enzyme failure. Several phenotypes can be distinguished on the basis of clinical onset and manifestations. Childhood cerebral X-linked ALD is the most severe phenotype, resulting in rapid neurologic deterioration and early death. Patients with this disease may be hospitalized with far-advanced central nervous system (CNS) lesions or may complain of symptoms similar to those of certain psychiatric disorders, possibly leading to a wrong diagnosis. Although the general prognosis for patients with childhood cerebral X-linked ALD is still poor, new treatment modalities have been introduced, some of which are helpful in relieving clinical symptoms and prolonging life. With the introduction of these new therapies and increased clinical detection of childhood cerebral X-linked ALD, brain magnetic resonance (MR) imaging has become an essential tool for initial and follow-up evaluation. MR imaging allows early detection of CNS lesions and helps differentiate childhood cerebral X-linked ALD from other disorders. The characteristic MR imaging features of childhood cerebral X-linked ALD have been well documented, although most radiologists have limited experience with serial follow-up MR imaging in this context. Familiarity with the clinical-pathologic manifestations and progressive MR imaging features of childhood cerebral X-linked ALD will be helpful in evaluating affected patients.
© RSNA, 2005
Abbreviations: ALD = adrenoleukodystrophy, AMN = adrenomyeloneuropathy, CNS = central nervous system, FLAIR = fluid-attenuated inversion recovery, VLCFA = very long chain fatty acid
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Introduction
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X-linked adrenoleukodystrophy (ALD) is a genetically determined metabolic disorder that manifests clinically as dysfunctions of the central nervous system (CNS), adrenal glands, and testicles. These dysfunctions are related to excessive accumulation of very long chain fatty acid (VLCFA) in tissues and plasma, which is caused by the failure of oxidative degradation of VLCFA that normally takes place in peroxisomes (1). A peroxisome is an intracellular organelle measuring 0.5 µm in diameter that participates in important cellular functions such as ß-oxidation of VLCFA, plasmalogen production, bile acid synthesis, and glyoxylated detoxification (2). Peroxisomes are present in all cells except mature red blood cells and are especially abundant in the liver and kidneys. Peroxisomal disorders can be grouped into (a) disorders of peroxisomal biogenesis and maintenance, (b) multiple peroxisomal enzyme deficiency, and (c) single peroxisomal enzyme deficiency (2,3). The first group includes Zell-weger syndrome, neonatal ALD, and infantile Refsum disease. The second group includes rhizomelic chondrodysplasia punctata. X-linked ALD belongs to the third group, along with classic Refsum disease, hyperoxaluria type I, and acatalasemia.
On the basis of clinical onset and manifestations, X-linked ALD can be classified into several phenotypes (childhood, adolescent, and adult cerebral X-linked ALD; adrenomyeloneuropathy [AMN]; Addison disease–only type; asymptomatic type), each type having its own clinical features and prognosis (1,4). Childhood cerebral X-linked ALD is, clinically speaking, the most severe type. Patients with childhood cerebral X-linked ALD usually show normal development until they reach 4–10 years of age, at which time behavioral changes including memory impairment and emotional instability manifest to varying degrees, followed by progressive deterioration of the vision, hearing, and motor function (1,4). In addition to CNS symptoms, adrenal dysfunction or gonadal insufficiency may be seen. There is no therapeutic method for inducing complete cure, but early detection and follow-up medical care including diet control, medication, or bone marrow transplantation may modify the clinical course and prognosis (5).
Magnetic resonance (MR) imaging is essential for both initial and follow-up evaluation of childhood cerebral X-linked ALD (4,6,7). Although new MR imaging techniques such as diffusion-weighted imaging and MR spectroscopy have been shown to be clinically useful in patients with childhood cerebral X-linked ALD, conventional brain MR imaging with T1- and T2-weighted, proton-density–weighted, and fluid-attenuated inversion recovery (FLAIR) sequences is easily available and is being used more widely (4,8–14).
With increased clinical detection of the disease and the introduction of new treatment modalities, follow-up MR imaging has become an essential part of clinical care in patients with childhood cerebral X-linked ALD. There have been many reports describing MR imaging findings in childhood cerebral X-linked ALD (8–14). However, in spite of the clinical usefulness of this modality, there have been few reports with pictorial descriptions of MR imaging findings at serial follow-up evaluation (2).
In this article, we review the clinical manifestations of X-linked ALD. We also discuss X-linked ALD (particularly the childhood cerebral type) in terms of genetic and biochemical features, pathogenesis and pathologic abnormalities, diagnosis, and treatment. In addition, we discuss and illustrate brain MR imaging findings at initial and follow-up evaluation of affected patients.
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Clinical Manifestations of X-linked ALD
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Moser (1) reported that the prevalence of X-linked ALD was between one in 20,000 and one in 100,000 male births, and a European survey reported that the prevalence of this disease was at least one in 100,000 male births, with an overall prevalence of at least one in 200,000 (15). X-linked ALD has been identified in patients from all races and continents, with no apparent predilection for any one race (15).
The classification of phenotypes in X-linked ALD is based on patient age at symptom onset and the organs that are principally affected. Although the classification scheme is somewhat arbitrary, at least six variants can be distinguished: childhood cerebral X-linked ALD, adolescent cerebral X-linked ALD, AMN, adult cerebral X-linked ALD, Addison disease–only type, and asymptomatic (presymptomatic) type (1,4,7,15).
The relative frequency with which phenotypes occur has varied somewhat in previous studies (1,15). According to Moser (1), childhood cerebral X-linked ALD occurs most frequently (37% of cases), followed by AMN (32%), Addison disease–only type (13%), adolescent cerebral type (7%), asymptomatic type (7%), and adult cerebral type (3%). The clinical features of the various phenotypes are summarized in the Table.
Although the most prominent and common manifestations of X-linked ALD involve the CNS, adrenal or testicular manifestations are also important. About two-thirds of male patients with nervous system dysfunction have overt or subclinical adrenocortical insufficiency, which may precede, accompany, or follow the onset of neurologic symptoms. Virtually all affected men have overt or subclinical testicular dysfunction as well (15). Powers and Schaumburg (16) reported that gonadal insufficiency might be the first symptom of X-linked ALD.
Because of the X-linked mode of inheritance, almost all symptomatic patients with X-linked ALD are hemizygotic males. However, heterozygotic women may have clinical symptoms similar to those of AMN. The reported prevalence of X-linked ALD among heterozygotic women varies from 20% to 50% (1,15). Symptom onset usually occurs in the 4th decade of life. The clinical symptoms of heterozygotic women are much milder than those of hemizygotic males with AMN. At brain MR imaging, abnormalities of the white matter are found in 10%–20% of female carriers.
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Genetic and Biochemical Features
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In 1910, Haberfeld and Spieler presented the first clinical description of childhood cerebral X-linked ALD. Their patient was a previously healthy 6-year-old boy who developed disturbances in vision and deterioration in schoolwork, followed by neurologic deterioration in motor and cognitive functions. The patient’s older brother had died of a similar illness at 8 years of age (1). Schilder conducted the first postmortem pathologic study in 1913, which showed severe loss of myelin and accumulation of inflammatory cells in the involved brain tissue. Disease of the adrenal glands was not described in this study but was in later studies. For a long time after the first report, this disease was called by various names, including encephalitis periaxialis diffusa and Schilder’s disease. The term adrenoleukodystrophy was coined in 1970 (1).
The genetic features of X-linked ALD have been described since the 1960s. In 1964, Blaw et al (17) noted that all patients were male, and on the basis of pedigree analysis suggested that ALD is a genetically determined disorder with an X-linked mode of inheritance. In 1973, Schaumburg demonstrated unusual striations in adrenocortical cells at electron microscopy. These striations proved to represent inclusions containing cholesterol esterified with saturated VLCFA (18). These findings helped identify X-linked ALD as a kind of lipid storage disease. In 1980, it was revealed by means of genetic mapping that the gene related to ALD is located at Xq28, the terminal segment of the long arm of the X chromosome (1).
Biochemical studies in the 1980s proved impaired capacity to degrade VLCFA in X-linked ALD, a function that is normally performed in the peroxisomes (19). In 1993, Moser et al isolated the gene, which codes for a peroxisomal membrane protein that is referred to as ALD protein (1,2). Later, the action of ALD protein in facilitating the oxidative degradation of VLCFA was confirmed. ALD protein belongs to the adenosine triphosphate binding cassette transporter superfamily, and the ALD protein coding gene is called ABCD1. Mutation of ABCD1 causing deficiency of ALD protein is associated with the accumulation of VLCFA, particularly hexacosanoic acid (C26:0), in the brain, adrenal glands, and plasma (1,15). However, the exact mechanisms by which ALD protein deficiency leads to the accumulation of VLCFA and the development of X-linked ALD are not yet clear.
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Pathogenesis and Pathologic Abnormalities
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Although the genetic basis and biochemical abnormalities of X-linked ALD have already been revealed, its pathogenesis is not fully understood. The exact role of excessive VLCFA in causing pathologic abnormalities in the CNS, adrenal glands, and testicles is not clear. Characteristic findings are lamellar cytoplasmic inclusions in the brain macrophages, Schwann cells, Leydig cells, and adrenocortical cells. The lamellar inclusions consist of cholesterol esterified with VLCFA. In childhood cerebral X-linked ALD, CNS lesions are dominant and include extensive demyelination in the periventricular deep white matter (especially in the parieto-occipital areas), cavitation, and perivascular lymphocytic infiltrates (1,4,15). It has been postulated that demyelinating inflammation is mediated by cytokines (1). Unlike the deep white matter, the U fibers and cortex are spared (2,15). Involvement of the peripheral nervous system is uncommon and minimal in childhood cerebral X-linked ALD. Nerve disease in AMN consists of distal axonopathy with secondary degeneration of myelin in the most distal part of the axons. AMN affects the spinal cord and peripheral nerves. The pathologic changes in the CNS in childhood cerebral X-linked ALD resemble those seen in multiple sclerosis. Both diseases are characterized by a breakdown of myelin with relative sparing of the axons, accumulation of cholesterol ester, and perivascular inflammatory response with breakdown of the blood-brain barrier. However, childhood cerebral X-linked ALD differs from multiple sclerosis in that it is characterized by extensive and contiguous involvement of the cerebral hemispheres, inflammatory infiltrates located behind (as opposed to at) the active demyelinating edge, and a different pattern of inflammatory cytokine expression (15).
Affected white matter of the brain is divided histopathologically into three distinct zones: an outermost zone (Schaumburg zone 1), showing active destruction of the myelin sheath and lack of perivascular inflammatory cells; a middle layer zone (Schaumburg zone 2), showing perivascular inflammatory cells and demyelination with preservation of axons; and a central zone (Schaumburg zone 3), showing gliosis and scattered astrocytes with absence of oligodendroglia, axons, myelin, and inflammatory cells (2).
The earliest pathologic change in the adrenal glands is the appearance of cytoplasmic striations with lamellae in cortical cells of the fascicular and reticular zones. The lamellae represent precipitation of lipid protein aggregates containing cholesterol esterified with VLCFA. With advancement of disease, the adrenal glands show atrophic change.
In involved testicles, light microscopy demonstrates hypocellularity and maturation arrest in seminiferous tubules. Ultrastructural examination reveals vacuolation of Sertoli cell endoplasmic reticulum and germ cells. Leydig cells with cytoplasmic striations are detected in some patients, and there may be a reduction in the number of Leydig cells. Ultrastructural lamellae and lamellar-lipid profiles in Leydig cells are pathognomonic findings (20).
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Diagnosis
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Laboratory evaluation of the VLCFA level is a simple and reliable diagnostic test. The level of VLCFA, especially hexacosanoic acid (C26:0), is elevated in plasma, skin fibroblasts, erythrocytes, and leukocytes (1,15). Abnormal elevation of the plasma VLCFA level is demonstrated in 99.9% of hemizygotic males and 85% of heterozygotic female carriers (1). Most laboratories measure the absolute concentration of C26:0 as well as the C24:0/C22:0 and C26:0/C23:0 ratios. Molecular genetic testing (DNA linkage analysis) has been used primarily to determine carrier status in at-risk female relatives and for prenatal diagnosis when the nature of the familial mutation is known.
Adrenal function is abnormal in 90% of neurologically symptomatic patients with childhood cerebral X-linked ALD and in 70% of AMN patients (15). The most sensitive laboratory evidences for adrenal dysfunction are elevated plasma adrenocorticotropic hormone concentration and impaired rise of plasma cortisol concentration in response to the administration of adrenocorticotropic hormone. In heterozygotic females, adrenal function is usually normal.
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Treatment
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Three treatment modalities are generally used in patients with childhood cerebral X-linked ALD. The first treatment is dietary therapy, which includes a very low-fat diet and consumption of Lorenzo’s oil (21–24). The Lorenzo’s oil reduces the level of plasma VLCFA to the normal range. It is believed that lessening the amounts of plasma VLCFAs will prevent their accumulation in the body, thereby halting the demyelinating change in the CNS and sparing the patient from disease progression. This approach may help prevent the disorder from manifesting clinically; however, a significant problem associated with Lorenzo’s oil is that, although it can lower the amount of VLCFA in the body, it does not cross the blood-brain barrier and therefore has no effect on the amount of VLCFA in the brain. Once a child is symptomatic and is encountering clinical difficulties, Lorenzo’s oil has no effect other than helping to prepare the child’s body for bone marrow transplantation. It seems that bone marrow transplantation is more successful if the child has a normal VLCFA level (21). The second treatment is lovastatin therapy. It has been discovered that lovastatin, a kind of anticholesterol drug, has the same effect as Lorenzo’s oil without a low-fat diet (25,26). Studies are ongoing to determine the clinical effects of lovastatin, and results are expected soon. The third treatment, bone marrow transplantation, is now accepted as an effective treatment that provides long-term clinical stabilization in patients with early brain symptoms (27,28). Replacement of diseased bone marrow with healthy marrow can prevent further damage from the genetically determined disease process of childhood cerebral X-linked ALD. However, bone marrow transplantation does not work if the disorder has progressed too far. Also, it is not recommended for patients with the adult onset form or neonatal form of X-linked ALD, and hormone replacement therapy is needed in patients with adrenal or gonadal insufficiency.
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MR Imaging Manifestations
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Initial Imaging
In 1994, Loes et al (7) described three classic patterns of brain MR imaging findings in X-linked ALD patients based on the anatomic location of the lesions. More recently, Loes et al (6) described five modified MR imaging patterns, with their relative frequencies, ages of affected patients, and patterns of progression at MR imaging. Pattern 1 was defined as primary involvement of the deep white matter in the parieto-occipital lobes and of the splenium of the corpus callosum (66% of cases, seen mainly in children), which may include lesions of the visual and auditory pathways according to the classic description (7). Pattern 2 was defined as involvement of the frontal lobe or genu of the corpus callosum (15.5% of cases, seen mainly in adolescents). Pattern 3 was defined as primary involvement of the frontopontine or corticospinal projection fibers (12% of cases, seen mainly in adults). Pattern 4 was defined as primary cerebellar white matter involvement (1% of cases, seen mainly in adolescents), whereas pattern 5 was defined as combined involvement of the parieto-occipital and frontal white matter (2.5%, seen mainly in children). Loes et al (7) also described MR imaging findings that did not conform to any of these five patterns.
Our series included 12 boys, whose ages at initial diagnosis ranged from 4 to 12 years. Two boys were asymptomatic in spite of an elevated plasma VLCFA level and brain lesions at MR imaging; they were evaluated because they had symptomatic brothers with childhood cerebral X-linked ALD.
Of the 12 patients in our series, seven definitely had pattern 1 MR imaging findings consisting of bilateral symmetric involvement of the parieto-occipital white matter. Other findings included involvement of the corpus callosum, visual pathway (optic radiation, lateral geniculate body), acoustic pathway (acoustic radiation, medial geniculate body, brachium of the inferior colliculus, lateral lemniscus), corticospinal tract in the brainstem, and middle cerebellar peduncles (Fig 1). One patient had bilateral involvement of the posterior limb of the internal capsule only (pattern 3) (Fig 2). MR imaging in another patient demonstrated lesions in the parieto-occipital white matter with rapid and prominent disease progression in the cerebellum and brainstem. In yet another patient, MR imaging demonstrated atrophic change in the frontal and parietal white matter with signal intensity change bilaterally in the parieto-occipital white matter. Unilateral involvement of the left-sided parieto-occipital white matter was demonstrated in one patient, and MR imaging findings were normal in one patient. The U fibers and cortex were spared in all cases. At gadolinium-enhanced T1-weighted MR imaging, the white matter lesions, especially in the parieto-occipital periventricular area, were enhanced at the peripheral portion corresponding to Schaumburg zone 2 (region of active inflammatory demyelination) (Fig 1g).
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Figure 1a. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1b. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1c. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1d. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1e. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1f. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1g. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1h. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1i. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1j. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1k. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 1l. Childhood cerebral X-linked ALD in an 8-year-old boy with initial clinical findings of hearing impairment. (a–f) Initial T2-weighted MR images show confluent and symmetric bilateral hyperintense areas in the parieto-occipital deep white matter and in the splenium of the corpus callosum (a, b), increased signal intensity in the acoustic radiation (arrows in b), subtle changes in signal intensity in the brachium of the inferior colliculus (arrow in c) and lateral lemniscus (arrow in d), and involvement of the pyramidal tract in the pons and medulla oblongata (arrows in e and f). (g) Initial contrast material–enhanced T1-weighted MR image shows strong enhancement in the middle layer of the lesion (Schaumburg zone 2) (white arrow). Zones 1 (solid black arrows) and 3 (open arrow) are not enhanced. These initial MR imaging findings suggested childhood cerebral X-linked ALD, and genetic-serologic test results confirmed the diagnosis. Although the patient underwent dietary and medical treatment, hearing impairment progressed rapidly. Visual disturbance also appeared 2 months after initial evaluation, and follow-up MR imaging was performed. (h–k) Follow-up MR images demonstrate more extensive bilateral signal intensity changes in the parieto-occipital white matter (h), interval growth of the lesions involving the brachium of the inferior colliculus (arrows in i, solid white arrow in j) and the lateral lemniscus (open arrow in j, arrow in k), and signal intensity change in the right optic tract (black arrow in j). The latter finding was not demonstrated at initial MR imaging. (l) MR image obtained 6 months after initial MR imaging shows more extensive bilateral signal intensity changes in the parieto-occipital white matter, along with atrophic change in the deep white matter.
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Figure 2a. Childhood cerebral X-linked ALD in a clinically asymptomatic 7-year-old boy. (a) On an initial brain MR image, the lesion is confined to the left parietopontine tract and to isolated white matter fibers of the corticospinal tract in the posterior limb of the internal capsule. (b) Follow-up MR image obtained 9 months later shows slight enlargement of the lesion (arrow) in the left parietopontine tract.
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Figure 2b. Childhood cerebral X-linked ALD in a clinically asymptomatic 7-year-old boy. (a) On an initial brain MR image, the lesion is confined to the left parietopontine tract and to isolated white matter fibers of the corticospinal tract in the posterior limb of the internal capsule. (b) Follow-up MR image obtained 9 months later shows slight enlargement of the lesion (arrow) in the left parietopontine tract.
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Follow-up Imaging
Eleven patients, two of whom were asymptomatic, began dietary therapy (very low-fat diet) immediately after initial diagnosis. One patient did not undergo any treatment because his parents refused further evaluation and treatment for him. Eight patients received additional medical therapy including administration of Lorenzo’s oil or lovastatin. None of the 12 patients underwent bone marrow transplantation. The mean follow-up period after initial diagnosis was 22 months (range, 6 months–6 years).
As discussed in previous reports, follow-up MR imaging may show improvement, stabilization, or aggravation of the lesions (5). Improvement means resolution or a reduction in the size of the lesions and may be demonstrated after treatment (5). However, in no case in our series did follow-up MR imaging show improvement or normalization of the lesions, even in clinically improved patients. Stabilization means no interval change in the lesions and no new lesions in other areas of the brain at follow-up MR imaging. In the patients in our series with lesion stabilization, the clinical manifestations were also stable. However, stabilization was usually transient; in most cases, aggravation of the lesions occurred in spite of medical treatment. In fact, aggravation of the lesions was the most common change at follow-up MR imaging. With progression of the disease, follow-up MR imaging showed lesions extending to adjacent brain tissue and new lesions in other areas of the brain. These new lesions appeared in the visual pathway (optic tract, optic radiation, lateral geniculate body), auditory pathway (medial geniculate body, brachium of the inferior colliculus, lateral lemniscus), projecting fibers of the brainstem, and cerebellum (Fig 1).
Progressive atrophic changes in the cerebrum, cerebellum, and brainstem were also seen in some patients and correlated directly with clinical deterioration (Figs 3, 4). The time interval to atrophic change was variable. In our series, atrophic change usually took 1 year or more, but such change developed rapidly in one patient, in whom follow-up MR images demonstrated severe atrophic change in the brain compared with MR images obtained 7 months earlier (Fig 5).
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Figure 3a. Childhood cerebral X-linked ALD in an 8-year-old boy whose initial symptoms were similar to those of anxiety disorder. (a–c) Initial MR images demonstrate confluent hyperintense areas in the parieto-occipital white matter. The U fibers are completely spared in all areas. These findings, along with serologic testing, helped confirm the diagnosis. The patient subsequently underwent diet therapy. MR imaging performed 6 months later showed no remarkable interval change. (d, e) MR images obtained 3 years after initial diagnosis with the patient in a near-vegetative state show severe atrophic change in the cerebral hemispheres and cerebellum.
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Figure 3b. Childhood cerebral X-linked ALD in an 8-year-old boy whose initial symptoms were similar to those of anxiety disorder. (a–c) Initial MR images demonstrate confluent hyperintense areas in the parieto-occipital white matter. The U fibers are completely spared in all areas. These findings, along with serologic testing, helped confirm the diagnosis. The patient subsequently underwent diet therapy. MR imaging performed 6 months later showed no remarkable interval change. (d, e) MR images obtained 3 years after initial diagnosis with the patient in a near-vegetative state show severe atrophic change in the cerebral hemispheres and cerebellum.
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Figure 3c. Childhood cerebral X-linked ALD in an 8-year-old boy whose initial symptoms were similar to those of anxiety disorder. (a–c) Initial MR images demonstrate confluent hyperintense areas in the parieto-occipital white matter. The U fibers are completely spared in all areas. These findings, along with serologic testing, helped confirm the diagnosis. The patient subsequently underwent diet therapy. MR imaging performed 6 months later showed no remarkable interval change. (d, e) MR images obtained 3 years after initial diagnosis with the patient in a near-vegetative state show severe atrophic change in the cerebral hemispheres and cerebellum.
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Figure 3d. Childhood cerebral X-linked ALD in an 8-year-old boy whose initial symptoms were similar to those of anxiety disorder. (a–c) Initial MR images demonstrate confluent hyperintense areas in the parieto-occipital white matter. The U fibers are completely spared in all areas. These findings, along with serologic testing, helped confirm the diagnosis. The patient subsequently underwent diet therapy. MR imaging performed 6 months later showed no remarkable interval change. (d, e) MR images obtained 3 years after initial diagnosis with the patient in a near-vegetative state show severe atrophic change in the cerebral hemispheres and cerebellum.
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Figure 3e. Childhood cerebral X-linked ALD in an 8-year-old boy whose initial symptoms were similar to those of anxiety disorder. (a–c) Initial MR images demonstrate confluent hyperintense areas in the parieto-occipital white matter. The U fibers are completely spared in all areas. These findings, along with serologic testing, helped confirm the diagnosis. The patient subsequently underwent diet therapy. MR imaging performed 6 months later showed no remarkable interval change. (d, e) MR images obtained 3 years after initial diagnosis with the patient in a near-vegetative state show severe atrophic change in the cerebral hemispheres and cerebellum.
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Figure 4a. Childhood cerebral X-linked ALD in a 9-year-old boy in whom the disease had been diagnosed with serologic testing and genetic study 2 years earlier. Although the patient had a symptomatic older brother with childhood cerebral X-linked ALD, he himself remained asymptomatic throughout the 2-year follow-up period. (a–c) Initial brain MR (FLAIR) images show subtle bilateral signal intensity changes in the parieto-occipital deep white matter and in the splenium of the corpus callosum. (d–f) On brain MR images obtained 7 months later, the lesions in the parieto-occipital white matter seem to be aggravated. New signal intensity changes are also demonstrated in the left medial geniculate body (arrow in e), lateral lemniscus (arrowhead in f), and brachium of the inferior colliculus (arrow in f). MR imaging performed 5 months later showed no interval change.
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Figure 4b. Childhood cerebral X-linked ALD in a 9-year-old boy in whom the disease had been diagnosed with serologic testing and genetic study 2 years earlier. Although the patient had a symptomatic older brother with childhood cerebral X-linked ALD, he himself remained asymptomatic throughout the 2-year follow-up period. (a–c) Initial brain MR (FLAIR) images show subtle bilateral signal intensity changes in the parieto-occipital deep white matter and in the splenium of the corpus callosum. (d–f) On brain MR images obtained 7 months later, the lesions in the parieto-occipital white matter seem to be aggravated. New signal intensity changes are also demonstrated in the left medial geniculate body (arrow in e), lateral lemniscus (arrowhead in f), and brachium of the inferior colliculus (arrow in f). MR imaging performed 5 months later showed no interval change.
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Figure 4c. Childhood cerebral X-linked ALD in a 9-year-old boy in whom the disease had been diagnosed with serologic testing and genetic study 2 years earlier. Although the patient had a symptomatic older brother with childhood cerebral X-linked ALD, he himself remained asymptomatic throughout the 2-year follow-up period. (a–c) Initial brain MR (FLAIR) images show subtle bilateral signal intensity changes in the parieto-occipital deep white matter and in the splenium of the corpus callosum. (d–f) On brain MR images obtained 7 months later, the lesions in the parieto-occipital white matter seem to be aggravated. New signal intensity changes are also demonstrated in the left medial geniculate body (arrow in e), lateral lemniscus (arrowhead in f), and brachium of the inferior colliculus (arrow in f). MR imaging performed 5 months later showed no interval change.
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Figure 4d. Childhood cerebral X-linked ALD in a 9-year-old boy in whom the disease had been diagnosed with serologic testing and genetic study 2 years earlier. Although the patient had a symptomatic older brother with childhood cerebral X-linked ALD, he himself remained asymptomatic throughout the 2-year follow-up period. (a–c) Initial brain MR (FLAIR) images show subtle bilateral signal intensity changes in the parieto-occipital deep white matter and in the splenium of the corpus callosum. (d–f) On brain MR images obtained 7 months later, the lesions in the parieto-occipital white matter seem to be aggravated. New signal intensity changes are also demonstrated in the left medial geniculate body (arrow in e), lateral lemniscus (arrowhead in f), and brachium of the inferior colliculus (arrow in f). MR imaging performed 5 months later showed no interval change.
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Figure 4e. Childhood cerebral X-linked ALD in a 9-year-old boy in whom the disease had been diagnosed with serologic testing and genetic study 2 years earlier. Although the patient had a symptomatic older brother with childhood cerebral X-linked ALD, he himself remained asymptomatic throughout the 2-year follow-up period. (a–c) Initial brain MR (FLAIR) images show subtle bilateral signal intensity changes in the parieto-occipital deep white matter and in the splenium of the corpus callosum. (d–f) On brain MR images obtained 7 months later, the lesions in the parieto-occipital white matter seem to be aggravated. New signal intensity changes are also demonstrated in the left medial geniculate body (arrow in e), lateral lemniscus (arrowhead in f), and brachium of the inferior colliculus (arrow in f). MR imaging performed 5 months later showed no interval change.
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Figure 4f. Childhood cerebral X-linked ALD in a 9-year-old boy in whom the disease had been diagnosed with serologic testing and genetic study 2 years earlier. Although the patient had a symptomatic older brother with childhood cerebral X-linked ALD, he himself remained asymptomatic throughout the 2-year follow-up period. (a–c) Initial brain MR (FLAIR) images show subtle bilateral signal intensity changes in the parieto-occipital deep white matter and in the splenium of the corpus callosum. (d–f) On brain MR images obtained 7 months later, the lesions in the parieto-occipital white matter seem to be aggravated. New signal intensity changes are also demonstrated in the left medial geniculate body (arrow in e), lateral lemniscus (arrowhead in f), and brachium of the inferior colliculus (arrow in f). MR imaging performed 5 months later showed no interval change.
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Figure 5a. Childhood cerebral X-linked ALD in a 12-year-old boy. The diagnosis was delayed because the patient’s initial symptoms were similar to those of behavioral disorder. (a–d) Initial MR images obtained 1 year after the onset of symptoms show focal bilateral signal intensity changes in the posterior limb of the internal capsule (a), involvement of the pyramidal tract in the pons (arrows in b and c) and medulla oblongata (arrows in d), and bilateral signal intensity change with mild atrophy in the middle cerebellar peduncles and adjacent cerebellum (c). Continuous medical care was advised, but the patient’s parents refused further evaluation and treatment for their son. Seven months later, the patient was admitted to the emergency department due to poor general condition and severe neurologic deterioration. (e–h) MR images show extensive bilateral lesion changes in the internal capsule (e) and upper pons (f) as well as severe atrophic change in the cerebellum and pons (g, h).
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Figure 5b. Childhood cerebral X-linked ALD in a 12-year-old boy. The diagnosis was delayed because the patient’s initial symptoms were similar to those of behavioral disorder. (a–d) Initial MR images obtained 1 year after the onset of symptoms show focal bilateral signal intensity changes in the posterior limb of the internal capsule (a), involvement of the pyramidal tract in the pons (arrows in b and c) and medulla oblongata (arrows in d), and bilateral signal intensity change with mild atrophy in the middle cerebellar peduncles and adjacent cerebellum (c). Continuous medical care was advised, but the patient’s parents refused further evaluation and treatment for their son. Seven months later, the patient was admitted to the emergency department due to poor general condition and severe neurologic deterioration. (e–h) MR images show extensive bilateral lesion changes in the internal capsule (e) and upper pons (f) as well as severe atrophic change in the cerebellum and pons (g, h).
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Figure 5c. Childhood cerebral X-linked ALD in a 12-year-old boy. The diagnosis was delayed because the patient’s initial symptoms were similar to those of behavioral disorder. (a–d) Initial MR images obtained 1 year after the onset of symptoms show focal bilateral signal intensity changes in the posterior limb of the internal capsule (a), involvement of the pyramidal tract in the pons (arrows in b and c) and medulla oblongata (arrows in d), and bilateral signal intensity change with mild atrophy in the middle cerebellar peduncles and adjacent cerebellum (c). Continuous medical care was advised, but the patient’s parents refused further evaluation and treatment for their son. Seven months later, the patient was admitted to the emergency department due to poor general condition and severe neurologic deterioration. (e–h) MR images show extensive bilateral lesion changes in the internal capsule (e) and upper pons (f) as well as severe | |
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Abstract
Introduction
