Neuroimaging Findings in Patients with Mucopolysaccharidosis: What You Really Need to Know 1

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1 NEUROLOGIC/HEAD AND NECK IMAGING 1448 Neuroimaging Findings in Patients with Mucopolysaccharidosis: What You Really Need to Know 1 Roberta Reichert, MD Lillian Gonçalves Campos, MD Filippo Vairo, MD, PhD Carolina Fischinger Moura de Souza, MD, PhD Juliano Adams Pérez, MD, MSc Juliana Ávila Duarte, MD, MSc Fernando Araujo Leiria, MD Maurício Anés, BSc Leonardo Modesti Vedolin, MD, PhD Abbreviations: CNS = central nervous system, CSF = cerebrospinal fluid, FLAIR = fluid-attenuated inversion-recovery, GAG = glycosaminoglycan, MPS = mucopolysaccharidosis RadioGraphics 2016; 36: Published online /rg Content Codes: 1 From the Divisions of Radiology (R.R., L.G.C., J.A.P., J.A.D., F.A.L., L.M.V.), Genetics (F.V., C.F.M.d.S.), and Medical Physics and Radiation Protection (M.A.), Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos St, Porto Alegre, Rio Grande do Sul , Brazil; and Postgraduate Program in Medical Sciences of Federal University of Rio Grande do Sul, Porto Alegre, Brazil (L.G.C., J.A.P., L.M.V.). Presented as an education exhibit at the 2014 RSNA Annual Meeting. Received June 5, 2015; revision requested October 13; revision received November 16; accepted December 2. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspondence to R.R. ( roberta_reichert@hotmail.com). RSNA, 2016 This copy is for personal use only. To order printed copies, contact reprints@rsna.org SA-CME LEARNING OBJECTIVES After completing this journal-based SA-CME activity, participants will be able to: Discuss the pathophysiologic principles of MPS. Identify the characteristic neuroimaging findings of MPS on brain MR images. List the main abnormalities noted on spine MR images in patients with MPS. See Mucopolysaccharidosis (MPS) is an inherited metabolic disease and a member of the group of lysosomal storage disorders. Its hallmark is a deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). The products of GAG degradation accumulate within lysosomes and in the extracellular space, thereby interfering with the degradation of other macromolecules. This process leads to chronic degeneration of cells, which in turn affects multiple organs and systems. There are seven distinct types of MPS (I, II, III, IV, VI, VII, and IX), which are divided into subtypes according to the deficient enzyme and the severity of the clinical picture. Although clinical manifestations vary considerably among the different types of MPS, the central nervous system (CNS) is characteristically affected, and magnetic resonance (MR) imaging is the method of choice to evaluate brain and spinal cord abnormalities. Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, cervical spinal canal stenosis with or without spinal cord compression and myelopathy, and bone abnormalities in the skull and spine (dysostosis multiplex) are typical imaging findings described in the literature and reviewed in this article. The differential diagnosis of MPS is limited because the constellation of imaging findings is highly suggestive. Thus, radiologists should be aware of its typical neuroimaging findings so they can recognize cases not yet diagnosed, exclude other metabolic diseases, monitor CNS findings over time, and assess treatment response. RSNA, 2016 radiographics.rsna.org Introduction Mucopolysaccharidosis (MPS) is an inherited metabolic disease and a member of the group of lysosomal storage disorders. Its hallmark is a deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs), owing to mutations in genes encoding lysosomal hydrolases (1,2). Partially degraded GAGs accumulate within lysosomes and in the extracellular space, interfering with the degradation of other macromolecules, which also accumulate. This process leads to chronic degeneration of cells, gradually affecting multiple organs and systems, especially the skeletal system, liver, spleen, heart, eyes, and central nervous system (CNS) (3,4). There are seven distinct types of MPS (I, II, III, IV, VI, VII, and IX), which are divided further into subtypes according to the deficient enzyme and severity of the clinical picture (1,3,4). The overall estimated incidence is one in individuals, although the incidence of each MPS type separately is much lower, on the order of one in to one in individuals (3,5). MPS is inherited via an

2 RG Volume 36 Number 5 Reichert et al 1449 TEACHING POINTS Mucopolysaccharidosis (MPS) is an inherited metabolic disease and a member of the group of lysosomal storage disorders. Its hallmark is a deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs), owing to mutations in genes encoding lysosomal hydrolases. Partially degraded GAGs accumulate within lysosomes and in the extracellular space, interfering with the degradation of other macromolecules, which also accumulate. This process leads to chronic degeneration of cells, gradually affecting multiple organs and systems, especially the skeletal system, liver, spleen, heart, eyes, and central nervous system (CNS). Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, and cervical spinal canal stenosis with or without spinal cord compression or myelopathy are typical imaging findings of MPS. In association, bone abnormalities in the skull and spine (dysostosis multiplex) are often present in these patients. Partially degraded GAGs accumulate throughout the body, including in the leptomeninges, which impair drainage of interstitial fluid from the brain parenchyma. The perivascular spaces then become distended with a mixture of CSF, interstitial fluid, and GAGs. At MR imaging, white matter lesions are nonspecific findings and appear as focal or confluent areas of T1 hypointensity and T2-FLAIR (fluid-attenuated inversion-recovery) hyperintensity. Periventricular white matter is the most common site of involvement, but these lesions can occur anywhere in the brain, including the subcortical white matter and the white matter of various brain lobes. Some authors describe the peritrigonal region as a common site for or a frequent initial area of white matter lesions. However, this information is not reported in most articles about neuroimaging findings of MPS. Symmetric distribution is a common feature. White matter lesions may coalesce and become larger and more diffuse, simulating the involvement pattern of leukodystrophy. MPS predisposes patients to atlantoaxial instability, which results from the association of odontoid dysplasia (ranging from hypoplasia to aplasia) with ligamentous laxity, especially the transverse ligament of the atlas. The severity of atlantoaxial instability influences the degree of ligamentous hypertrophy. Thus, the more severe that atlantoaxial instability is, the more that ligamentous hypertrophy will be. Another consequence of atlantoaxial instability and ligamentous hypertrophy is invagination of the posterior arch of C1, which is located more anteriorly than usual, contributing to narrowing of the spinal canal. In addition, there is thickening of the dura and paraspinal ligaments due to GAG deposition. All mechanisms mentioned above contribute to narrowing of the foramen magnum and upper cervical canal and may lead to compressive myelopathy. autosomal pattern. The exception is MPS type II, which exhibits X-linked transmission (3,6). Table 1 summarizes the main genetic and metabolic aspects of MPS types (3,7). In this article, we present an overview of the neuroimaging findings characteristic of the various MPS types and review their pathophysiology, with representative images of confirmed cases from the radiology and genetics divisions of our hospital. We also briefly describe the MR imag- ing protocol and imaging follow-up used in our institution in patients with MPS. Clinical Features of MPS Clinical manifestations vary considerably among the different types of MPS and are summarized in Table 2. MPS types I, II, III, and VII are characterized by cognitive impairment, including delayed psychomotor development or neurologic regression in the first years of life. Unlike the other types of MPS, MPS type III has a mild manifestation or no other clinical manifestation, whereas MPS types I, II, and VII are accompanied by multisystemic abnormalities, especially skeletal involvement (3,4,6). Classically, MPS I is subdivided into three forms depending on clinical presentation and severity of neurologic impairment. The most severe phenotype of MPS I is Hurler syndrome, which is characterized by substantially affected cognitive development and associated with multisystemic manifestations, including skeletal, respiratory, and cardiac disorders. Symptoms begin after birth and progress rapidly. If symptoms are not treated properly, the disease usually leads to death before 10 years of age. Hurler-Scheie syndrome is the intermediate form of this disease. Patients with this syndrome have no apparent cognitive alteration. Other systemic manifestations in Hurler-Scheie syndrome are less severe than those in patients with Hurler syndrome and begin in childhood. Patients usually survive until the 2nd or 3rd decade of life. Finally, Scheie syndrome is the most attenuated phenotype of MPS I, as the symptoms appear later and patients have no cognitive decline and generally survive to adulthood. Multiple factors may contribute to this large clinical variability, including the type of mutation in the MPS I gene (IDUA), residual enzyme activity, and possibly environmental factors (2,3,6). In regard to neurologic involvement, MPS type II can also be divided into severe (neuropathic) and mild (nonneuropathic) forms. In the former, patients may experience developmental delay and neurologic regression. In the latter, the CNS is either not affected or mildly affected, and patients have normal intelligence (2,6). Unlike patients with one of the MPS types mentioned above, patients with MPS types IV or VI usually do not have cognitive impairment. Neurologic disorders are often secondary to bone changes, and myelopathy is the main clinical manifestation in these patients (3,4). To date, only a few cases of MPS type IX have been reported in the literature, and the main clinical feature reported is joint involvement (3). Importantly, MPS type V and VIII classifications are

3 1450 September-October 2016 radiographics.rsna.org Table 1 : Classification of MPS MPS Type Eponym Enzyme Deficiency GAGs Stored Gene I II IH IHS IS IIA* IIB* III IIIA IIIB IIIC IIID IV IVA VI IVB Hurler syndrome Hurler-Scheie syndrome Scheie syndrome Hunter (severe) syndrome Hunter (mild) syndrome Sanfilippo syndrome A Sanfilippo syndrome B Sanfilippo syndrome C Sanfilippo syndrome D Morquio syndrome A Morquio syndrome B Maroteaux-Lamy syndrome a-l-iduronidase a-l-iduronidase a-l-iduronidase Iduronate-2- sulfatase Iduronate-2- sulfatase Heparan N- sulfatase a-n-acetylglucosaminidase Heparan-a-glucosaminide N-acetyltransferase N-acetylglucosamine-6-sulfatase Galactose 6- sulfatase Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Dermatan sulfate, heparan sulfate Genetic Locus Genetic Inheritance IDUA 4p16.3 Autosomal IDUA 4p16.3 Autosomal IDUA 4p16.3 Autosomal IDS Xq28 X-linked IDS Xq28 X-linked Heparan sulfate SGSH 17q25.3 Autosomal Heparan sulfate NAGLU 17q21.2 Autosomal Heparan sulfate HGSNAT 8p11.2- Autosomal p11.1 Heparan sulfate GNS 12q14.3 Autosomal Keratan sulfate, chondroitin sulfate GALNS 16q24.3 Autosomal b-galactosidase Keratan sulfate GLB1 3p22.3 Autosomal Arylsulfatase B Dermatan sulfate, ARSB 5q14.1 Autosomal chondroitin sulfate VII Sly syndrome b-glucuronidase Dermatan sulfate, heparan sulfate, chondroitin sulfate IX Natowicz syndrome GUSB 7q11.21 Autosomal Hyaluronidase Hyaluronan HYAL1 3p21.31 Autosomal *Severe (IIA) and mild (IIB) forms of MPS II can also be referred to as the neuropathic and nonneuropathic forms, respectively. no longer used. MPS V was reclassified as Scheie syndrome, and the report that initially described a case of MPS VIII was retracted (3,6,8). Measurement of urinary GAG concentration is the screening method performed in a patient clinically suspected of having MPS (2,3). A positive result is indicative of MPS. Apparently normal levels can occur due to sample dilution and lack of sensitivity of some assays (3). Thus, a negative test result is not sufficient to exclude a diagnosis, especially in a suggestive clinical setting. The diagnosis of MPS is confirmed with the help of an enzyme assay, in which the deficient enzymatic activity is determined, allowing identification of the particular type of MPS (2,3). After diagnosis of MPS, DNA testing for genotype identification can proceed, enabling family genetic counseling (2). Enzyme replacement therapy via intravenous administration of the deficient enzyme was initially developed for use in patients with MPS types I or II (9). More recently, it was approved for use in patients with MPS VI (3). A major limitation of enzyme replacement therapy is the

4 RG Volume 36 Number 5 Reichert et al 1451 Table 2: Main Clinical Manifestations of MPS Organ or System CNS Skeletal system Eyes Other systems Clinical Manifestations Cognitive impairment, behavioral problems, compressive myelopathy Dysostosis multiplex, coarse facial features Corneal opacities, retinopathy, glaucoma Hepatosplenomegaly, heart disease, reduced lung function, hearing loss Table 3: Proposed MR Imaging Protocol Summary for Patients with MPS Brain MR imaging 3D T1-weighted images obtained before and after intravenous administration of gadoliniumcontaining contrast material reconstructed in axial, sagittal, and coronal planes 3D T2-weighted images reconstructed in axial, sagittal, and coronal planes Axial FLAIR Axial gradient-recalled echo or susceptibilityweighted imaging Axial diffusion-weighted imaging with apparent diffusion coefficient mapping Cervical, thoracic, and lumbosacral spine MR imaging Sagittal T1-weighted Sagittal T2-weighted Coronal T2-weighted Axial T2-weighted Axial T1-weighted with fat suppression obtained before and after intravenous administration of gadolinium-containing contrast material lack of an effect on the CNS, as its penetration is prevented by the blood-brain barrier (1,10). Bone marrow transplantation has emerged as a treatment option in these patients. The use of bone marrow transplantation was first reported in 1981 in a patient with MPS I and was associated with improvement in clinical and biochemical parameters (11). In patients with severe alterations in the spine, orthopedic surgical procedures, such as arthrodesis and spinal decompression, may be required (12). MR Imaging and MPS Magnetic resonance (MR) imaging is the method of choice in the evaluation of brain and spinal cord abnormalities in patients with MPS, just as it is in patients with other metabolic disorders (5,13). Although enzyme assay is the main test used to diagnose MPS, identification, morphologic characterization, and analysis of the distribution of CNS lesions at MR imaging may indicate this diagnosis, especially in association with clinical data, and may be used to exclude other metabolic diseases (2,3,5,13). MR imaging also plays a fundamental role in monitoring of CNS findings over time and in evaluation of treatment response (5,13). Patients who receive a diagnosis of MPS or who are suspected of having MPS should undergo MR imaging of the entire neuraxis for complete evaluation because manifestations of this disease are not limited to the brain. We must remember that many patients with MPS require anesthesia before the examination can be performed and that there is a well-documented association in the literature between MPS and difficult airway management (14). Thus, the MR imaging protocol should be optimized so that it can be performed in the shortest time possible. A proposed protocol is summarized in Table 3. Neuroimaging Findings MPS has characteristic neuroimaging features, which are best evaluated at MR imaging (Table 4) (5). Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, and cervical spinal canal stenosis with or without spinal cord compression or myelopathy are typical imaging findings of MPS. In association, bone abnormalities in the skull and spine (dysostosis multiplex) are often present in these patients (4,15,16). Brain and spine involvement vary according to the type of MPS, as will be discussed later in this article in the form of representative cases. Table 5 summarizes the main imaging findings in each type of MPS. A brief review of the pathophysiology of each of these findings is also presented. Enlarged Perivascular Spaces Perivascular spaces, also known as Virchow-Robin spaces, surround the vessel walls on their way from the subarachnoid space through the brain parenchyma and are delimited externally by the subpial space (17). There is no direct communication between perivascular spaces and the subarachnoid space (18). Perivascular spaces contain interstitial fluid and serve as the lymphatic drainage pathways of the brain (19). Partially degraded GAGs accumulate throughout the body, including in the leptomeninges, which impair drainage of interstitial fluid from the brain parenchyma. The perivascular spaces then become distended with a mixture of CSF, interstitial fluid, and GAGs (4,20,21). It has been suggested that enlarged perivascular spaces are

5 1452 September-October 2016 radiographics.rsna.org Table 4: Neuroimaging Findings in MPS and MR Imaging Appearance Neuroimaging Finding Enlarged perivascular space White matter lesions Hydrocephalus Cortical atrophy Cervical spinal canal stenosis Bone abnormalities in the skull and spine MR Imaging Appearance Cribriform or fusiform cystic lesions isointense to cerebrospinal fluid (CSF) at all sequences; diameters ranging from 2 mm to more than 8 mm Focal or confluent areas of T1 hypointensity and T2-FLAIR hyperintensity Dilatation of ventricular spaces typically associated with enlarged subarachnoid spaces Enlargement of cortical sulci and fissures Dysplastic odontoid process associated with soft-tissue mass, which is usually iso- or hypointense on T1-weighted images and hypointense on T2-weighted images, with or without spinal cord compression and myelopathy; functional imaging of the cervical spine may be necessary to better depict atlantoaxial instability Wedge-shaped vertebral bodies, platyspondyly, anterior beaking with posterior scalloping of vertebral bodies (bullet-shaped vertebrae), intervertebral disk changes, gibbus deformity, scoliosis, odontoid dysplasia, thickening of the diploe, morphologic abnormalities of the sella turcica, and macrocephaly Table 5: Neuroimaging Findings according to Type of MPS Type of MPS MPS I MPS II Enlarged Perivascular Space White Matter Lesions Hydrocephalus Brain Atrophy MPS III Typical MPS IV Uncharacteristic Typical Spinal Canal Stenosis Typical Typical Typical Typical Typical Uncharacteristic MPS VI Typical Typical Typical Typical MPS VII Uncharacteristic Uncharacteristic Uncharacteristic Typical pro- MPS IX Uncharacteristic nounced Uncharacteristic Uncharacteristic Uncharacteristic Uncharacteristic Dysostosis Multiplex Uncharacteristic Uncharacteristic a sensitive marker of abnormal CSF circulation and represent its initial phase, which will result in ventriculomegaly in later stages of MPS (20). Enlarged perivascular spaces have been described in patients with MPS I, II, III, or VI and are more accentuated in patients with MPS I or II (16,22). There is limited information in the literature about the clinical importance of enlarged perivascular spaces. A study comparing patients with MPS and cognitive decline with patients with MPS but without cognitive decline found no significant difference in frequency of enlarged perivascular spaces between the groups (23). At MR imaging, perivascular spaces follow the signal intensity of CSF for all pulse sequences and often have a radial orientation from the subependymal region toward the cortex (Fig 1a) (17,24,25). They appear as numerous cribriform and/or fusiform cystic lesions, with diameters usually ranging from 2 to 8 mm (15,16,20). Giant perivascular spaces exceeding 8 mm in diameter also have been described (20,26). Periventricular white matter is the most common site of involvement, although enlarged perivascular spaces can be found in the corpus callosum, basal ganglia, subcortical white matter, thalami, or brainstem (Fig 1b, 1c) (15,16). Enlarged perivascular spaces also have been reported in the cerebellar white matter and in adjacent dentate nuclei (27).

6 RG Volume 36 Number 5 Reichert et al 1453 Figure 1. (a) MPS IIIC in a 10-year-old boy. Axial T2- weighted MR image of the brain shows cystic fusiform dilated perivascular space (black arrow). Additional findings include enlargement ( ) of cortical sulci and thickening (white arrow) of the diploe. This patient showed signs and symptoms of neurologic regression, such as recent difficulty in speaking and walking. (b, c) Nonneuropathic MPS II in a 20-year-old man. Axial T2-weighted (b) and sagittal T1-weighted (c) MR images of the brain show marked perivascular space enlargement in the thalami (arrow in b, arrowhead in c), corpus callosum (black arrow in c), and subcortical white matter (white arrow in c). Importantly, enlarged perivascular spaces are not a specific finding of MPS and are found in several other entities of vascular, inflammatory, infectious, or neoplastic origin. Furthermore, small perivascular spaces (<2 mm) are usually found in healthy individuals of all ages, and they become more frequent and larger (>2 mm) with advanced age (17). Abnormal signal intensity in the surrounding white matter is present in patients with MPS and helps to differentiate enlarged perivascular spaces associated with MPS from normal perivascular spaces (17). In contrast to MPS, enlarged perivascular space rarely involve the corpus callosum in healthy individuals (28). In isolated cases of enlarged perivascular spaces, alternative diagnoses that should also be considered include cystic periventricular leukomalacia, hypomelanosis of Ito, velocardiofacial syndrome, and Lowe syndrome (17,29 31). White Matter Lesions White matter lesions are one of the most common findings described in patients with MPS and are related to deposition of partially degraded GAGs within neurons and oligodendrocytes in the CNS (4). Studies suggest the presence of myelin abnormalities in patients with MPS (32,33). However, the pathophysiologic process responsible for white matter lesions in these patients remains unclear. By definition, demyelination signifies pathologic loss of myelin. Hypomyelination and dysmyelination refer to reduction in myelin quantity and quality, respectively. It has been hypothesized that in patients with MPS, there is a structural anomaly

7 1454 September-October 2016 radiographics.rsna.org Figure 2. MPS I and neurologic impairment in a 3-year-old boy. Axial FLAIR MR image of the brain shows symmetric periventricular white matter lesions (arrows) adjacent to the frontal and occipital horns of the lateral ventricles. There is associated mild ventriculomegaly (*). Figure 3. MPS I in an 8-year-old girl. Axial FLAIR MR image of the brain shows abnormal high signal intensity (black *) in the periventricular and subcortical white matter, with associated ventriculomegaly (white *). in myelin. Thus, dysmyelination seems to be the most appropriate term to explain, at least in part, white matter lesions in patients with MPS (34). In MPS types I, II, III, and VII, white matter lesions appear in the first years of life. In patients with MPS IV or VI, however, these lesions may become apparent only in the 2nd decade of life and are generally less extensive (4,25,35). To our knowledge, there is no report of white matter lesions in patients with MPS type IX, which is essentially characterized by articular involvement (3). At MR imaging, white matter lesions are nonspecific findings and appear as focal or confluent areas of T1 hypointensity and T2-FLAIR (fluid-attenuated inversion-recovery) hyperintensity (Fig 2) (4,16). Periventricular white matter is the most common site of involvement, but these lesions can occur anywhere in the brain, including the subcortical white matter and the white matter in various brain lobes (Fig 3) (16,20,36). Some authors describe the peritrigonal region as a common site for or a frequent initial area of white matter lesions (23,37). However, this information is not reported in most articles about neuroimaging findings of MPS. Symmetric distribution is a common feature (20). White matter lesions may coalesce and become larger and more diffuse, simulating the involvement pattern of leukodystrophy (Fig 4) (37). Importantly, enlarged perivascular space and white matter lesions do not necessarily occur in combination (16,23). The relationship between the extent of white matter lesions and clinical findings is a controversial issue in the literature (20,23,36). Thus, studies with larger and more comprehensive samples of patients and quantitative MR imaging methods are needed to determine the potential correlation between white matter lesion load and clinical manifestations. The relationship between the extent of white matter injury and disease duration also has yielded conflicting results in the literature. Nevertheless, the largest study to analyze this topic found a positive association between extent of white matter lesions and duration of disease (5). Hydrocephalus Hydrocephalus in patients with MPS may be explained by two different mechanisms. First, the systemic accumulation of GAGs also affects the meninges, which may impair the function of arachnoid granulations, decreasing CSF reabsorption. Second, it has been hypothesized that abnormal bone proliferation at the skull base decreases cerebral venous outflow. One or both mechanisms lead to communicating hydrocephalus (4,5,20). It is typically more common and more in patients with MPS I or II and less frequent in patients with MPS III, IV, or VI (16). In general, communicating hydrocephalus in patients with MPS is slowly progressive and typically manifests as ventricular and subarachnoid space dilatation (Fig 5) (4,16,20,36). The lateral and third ventricles are most commonly affected (16). As a result of expansion of CSF spaces, macrocephaly is a common finding in patients with MPS (4). There may be enlargement of the optic nerve sheath as a consequence of hydrocephalus. If

8 RG Volume 36 Number 5 Reichert et al 1455 Figure 4. Axial FLAIR MR images of the brain in a girl with MPS type I. (a) Baseline MR image at 8 months of age shows hyperintense lesions (arrows) affecting the subcortical and periventricular white matter, simulating the MR imaging pattern of leukoencephalopathy. She underwent bone marrow transplantation at 2 years of age, with a substantial improvement in neurodevelopment. (b) Repeat MR image at 5 years of age shows a remarkable reduction in size of the white matter lesions (arrows). In both images, there is also prominence of the right posterior horn ventricle ( ) owing to ischemic alterations of unknown origin and diffuse mild ventricular enlargement. Figure 5. MPS II in a 6-year-old boy. Axial T2- weighted MR images at different levels show lateral ( ) and third ventricular (black arrow) dilatation and enlargement (white arrow) of the subarachnoid space. This patient had severe neurologic impairment and was dependent on others for all daily tasks. this process persists for a long time, it can result in optic nerve atrophy (4). The determination of need for surgical CSF shunt creation is individualized. To our knowledge, there is no established protocol to assess patients with MPS for the use of this procedure. In daily practice, imaging findings are correlated with clinical data, lumbar puncture, or both to assess for the presence of increased intracranial pressure. In the presence of recent neurologic deterioration or signs and symptoms of intracranial hypertension, creation of a CSF shunt is usually indicated (38). Creation of a ventriculoperitoneal shunt is the standard procedure and is a common imaging finding in patients with MPS (Fig 6), as are its complications (Fig 7) (38,39). Because of

9 1456 September-October 2016 radiographics.rsna.org Figure 6. MPS I in a 9-year-old girl. Coronal T1- weighted MR image of the brain shows a ventriculoperitoneal shunt catheter (arrow) from the left lateral ventricle to subcutaneous tissue. There is also significant enlargement ( ) of cortical sulci. Figure 7. MPS type II in an 8-year-old boy. Axial computed tomographic (CT) image of the brain shows bilateral large hemorrhagic subdural collections ( ) after ventriculoperitoneal shunt placement. There is little midline deviation (white arrow) to the right. A ventriculoperitoneal shunt catheter (black arrow) can be seen. Figure 8. MPS type II in a 10-year-old boy with severe neurologic regression. Axial T2- weighted MR images obtained at different levels of the brain show marked brain atrophy, characterized by enlargement of cortical sulci and fissures (*), with consequent ventriculomegaly. In the right occipital region, there is an extra-axial lesion (arrow) with signal intensity similar to that of CSF, most likely corresponding to an arachnoid cyst or enlargement of the subarachnoid space. the risk with this procedure of infection and mechanical complications (such as obstruction and tube migration), third ventriculostomy has been described as an alternative treatment (40). Brain Atrophy Brain atrophy is a common finding in patients with MPS; however, its pathophysiology is not well established (16,22). One of the main hypotheses is that neuronal death and gliosis are induced by the deposition of GAGs (5,16). Brain atrophy is more common in patients with MPS I, II, and III (especially those with MPS II or III), and appears during the first years of life. Although a less frequent and less severe finding, brain atrophy has also been described in patients with MPS VI (4,22,25). Imaging findings are mainly characterized by enlargement of cortical sulci and fissures (Fig 8) (25). Brain atrophy in patients with MPS is predominantly cortical and diffuse and may be symmetric or asymmetric (16).

10 RG Volume 36 Number 5 Reichert et al 1457 Figure 9. Flowchart shows mechanisms leading to cervical spinal canal stenosis in patients with MPS. We must remember that ventriculomegaly, which simply means dilatation of the ventricular system, can be the result of either hydrocephalus or brain atrophy; both conditions are usually described in, and can potentially coexist in, patients with MPS (41). One of our challenges is to differentiate between hydrocephalus, which refers to an expansion of CSF volume, and ventricular dilatation secondary to brain atrophy, in patients with MPS (25). Both entities manifest as ventriculomegaly in association with increased subarachnoid space (28). Furthermore, distinguishing between periventricular white matter lesions and transependymal edema due to increased CSF pressure is not always feasible (28). Finally, patients with MPS may have papilledema without intracranial hypertension, owing to GAG deposition in the sclera (42). In this scenario, correlation with clinical data and comparison with previous examinations are critical. The relationship between clinical manifestations or disease duration and severity of atrophic changes and/or ventriculomegaly is highly controversial in the literature, with conflicting results in different studies (5,20,23,28,36). Cervical Spinal Canal Stenosis Spinal canal stenosis is a characteristic finding of MPS and occurs most commonly at the level of the atlantoaxial joint (43). It also can occur in the thoracic or lumbar spine, although this is a less common finding (4,41). Spinal stenosis and compression are frequent and important findings in patients with MPS IV or VI. They can also be found in patients with MPS I and, less frequently, in patients with MPS II, III, or VII (4,16). The main clinical manifestations associated with stenosis of the craniocervical junction range from exercise intolerance and lower limb paresis to para- or quadriplegia and respiratory insufficiency of central origin (16,43). Spinal canal stenosis has a multifactorial origin. MPS predisposes patients to atlantoaxial instability, which results from the association of odontoid dysplasia (ranging from hypoplasia to aplasia) with ligamentous laxity, especially the transverse ligament of the atlas. The severity of atlantoaxial instability influences the degree of ligamentous hypertrophy. Thus, the more severe that atlantoaxial instability is, the more that ligamentous hypertrophy will be (4,15,16). Another consequence of atlantoaxial instability and ligamentous hypertrophy is invagination of the posterior arch of C1, which is located more anteriorly than usual, contributing to narrowing of the spinal canal (4,15). In addition, there is thickening of the dura and paraspinal ligaments due to GAG deposition (39,43,44). All mechanisms mentioned above contribute to narrowing of the foramen magnum and upper cervical canal and may lead to compressive myelopathy (Fig 9). MR imaging shows the dysplastic odontoid process associated with a surrounding soft-tissue mass, which is usually iso- or hypointense on T1-weighted images and hypointense on T2- weighted images (Fig 10) (4). The presence of myelopathy is characterized by abnormal signal intensity in the spinal cord (Figs 10, 11) (16). The signs and symptoms of myelopathy may not be related to the degree of spinal cord compression, since the neurologic deficit is usually milder than suggested by MR imaging (15). Cervical flexion and extension may be necessary to better depict the atlantoaxial instability (Fig 12) (41). Neurosurgical spinal decompression and stabilization are the primary methods used to treat spinal stenosis (45,46). However, the surgical anesthetic risk in patients with MPS should be considered. Currently, there is no standardized procedure among medical centers to evaluate these cases. To reduce the subjectivity of evaluation and to support therapeutic decisionmaking, some authors have proposed assessment scales with defined and reproducible criteria, using aspects of MR imaging, neurologic clinical

11 1458 September-October 2016 radiographics.rsna.org Figures 10, 11. (10) MPS type IVA in a 7-year-old girl. (a) Lateral radiograph of the cervical spine in flexion shows detachment between the anterior arch of C1 and the odontoid process, although the atlantoaxial predentate space (3 mm) is normal for her age. (b) Sagittal T1-weighted MR image of the cervical spine shows a large isointense soft-tissue mass (arrows) surrounding the short odontoid process and the anterior arch of C1, determining substantial reduction of spinal canal caliber and consequent compression of the spinal cord. (c, d) Sagittal (c) and axial (d) T2-weighted MR images of the cervical spine show areas of abnormal hyperintense signal (arrow) in the spinal cord at the level of C2, reflecting compressive myelopathy. (11) MPS type I in a 22-year-old woman with a history of previous laminectomy. (a, b) Sagittal T2-weighted MR images of the spine. The patient presented with a motor deficit in the upper and lower limbs. There is reduced diameter of the cervical and thoracic spinal canal accompanied by areas of hyperintensity (arrows) in the spinal cord at these levels, which is indicative of myelopathy. (c) Axial contrast material enhanced T1-weighted MR image. Impregnation of the epidural soft tissues around the thoracic spinal cord occurred after intravenous administration of contrast material. This shows an asymmetric thickening (arrow) that is greater on the right side, leading to reduction of thoracic spinal canal diameter. examination, and somatosensory evoked potentials of the median nerve (46). Bone Abnormalities in the Skull and Spine Involvement of the skeletal system is a major feature of MPS, and skeletal abnormalities are collectively referred to as dysostosis multiplex (3). GAG deposits in the skeletal system associated with defective bone maturation are the main pathophysiologic mechanisms involved (16). Dysostosis multiplex is described in patients with MPS I, II, IV, VI, or VII who pre sent with variable severity of involvement, even within

12 RG Volume 36 Number 5 Reichert et al 1459 Figure 12. MPS type I in a 22-year-old woman with a history of previous laminectomy (same patient as in Fig 11). Sagittal T1- weighted MR images of the cervical spine in the neutral position (a) and in flexion (b) show no modification in the atlantoaxial predentate space (arrow) with flexion. Figure 13. Vertebral body abnormalities in MPS type II. (a) MPS II in a 6-year-old boy. Lateral radiograph of the thoracic spine shows anterior beaking (white arrow) and posterior scalloping (black arrow). This condition is sometimes called bullet-shaped vertebrae. (b, c) MPS II in an 11-year-old boy. Lateral radiograph (b) and sagittal CT image (c) of the cervical spine show flattened vertebral bodies (arrows). This condition is sometimes called platyspondyly. the same family (41). MPS III is the major exception, as CNS involvement is its main feature and there is little or no somatic manifestation (6). MPS IX is the most recently defined subtype, with only a few cases having been reported in the literature. Its predominant feature is joint involvement, including joint effusion and periarticular soft-tissue masses (47,48). In this article, we focus on skeletal manifestations of the spine and skull. In the spine, MR imaging depicts various abnormalities involving the vertebral bodies. The main findings are wedge-shaped vertebral bodies, platyspondyly, and anterior beaking and posterior scalloping (bullet-shaped vertebrae) (Fig 13) (16,47). Intervertebral disk changes have also been reported, especially wide disk spaces, although disks are described as dehydrated and bulging or herniated (Fig 14) (15,16). These abnormalities can lead to various deformities and deviations of

13 1460 September-October 2016 radiographics.rsna.org the spinal axis, such as scoliosis and thoracolumbar kyphosis, which can reduce the caliber of the spinal canal and which may cause compressive myelopathy (12,45,47,49). Thoracolumbar kyphosis (or gibbus deformity) is a highly suggestive finding of MPS. It occurs because of little growth in the anterosuperior portion of the cranial lumbar vertebral bodies, resulting in a wedge-shaped deformity (Fig 15) (12). Odontoid dysplasia, described above, is also part of the spectrum of skeletal abnormalities in the spine (47). Skull abnormalities include thickening of the diploe (Figs 1a, 16), morphologic abnormalities at the skull base (such as the J-shaped appearance of the sella turcica [Fig 17]), and macrocephaly. The latter is closely related to hydrocephalus and expansion of CSF spaces (4,12,41,47). Cognitive alterations associated with dysostosis multiplex are not exclusive to MPS. These features can also be found in patients with other conditions, such as multiple sulfatase deficiency, glycoprotein degradation disorders, mucolipidosis, and monosialotetrahexosylganglioside (GM1) gangliosidosis (41,50). Posterior Fossa Findings Although less frequently reported in the literature, patients with MPS also may have abnormalities in the posterior fossa. Mega cisterna magna is the most common finding in the posterior fossa in MPS and is a frequent abnormality in patients with MPS II (Figs 17, 18) (16,28). Its main alternative diagnosis is arachnoid cyst, which can occur in both the supratentorial compartment and the posterior fossa (16). With regard to the dimensions of the infratentorial region, small posterior fossa and Chiari I malformation have been described in patients with MPS II, but these findings are much less common (28). Other reported findings in the posterior fossa of patients with MPS include enlarged perivascular space in the brainstem (Fig 19) and cerebellum, cerebellar white matter lesions, cerebellar hypoplasia, and macrocerebellum (27). Figures 14, 15. (14) MPS type IVA in a 21-year-old woman. Sagittal T2-weighted MR image of the spine shows deformity of vertebral bodies and posterior bulging of intervertebral disks, causing impression (arrows) on the spinal cord at multiple levels. This patient had no clinical signs of spinal cord compression. (15) MPS type VI in a 21-year-old man. Sagittal CT image shows thoracolumbar kyphosis (posterior gibbus) as the result of vertebral malformations. There is little growth of the anterosuperior portion of the cranial lumbar vertebrae, resulting in a wedge-shaped deformity (arrow). Imaging Follow-up Although imaging methods are essential in monitoring patients with MPS, the manner in which follow-up is performed is not uniform among medical institutions. Baseline brain and spine MR imaging and radiography of the cervical spine in flexion and extension are recommended (39). Most commonly, imaging studies are repeated according to disease progression and clinical judgment. A frequency of once every 1 3 years is suggested (12). At our institution, brain and spine MR imaging are performed at the time of diagnosis and are helpful in monitoring disease progression at follow-up examinations. Brain MR imaging usually is repeated once every 2 3 years or earlier if there are new clinical findings or if there is milestone regression. Spinal MR imaging is repeated if there are new symptoms, changes in the neurologic examination findings, or neurophysiologic abnormalities according to the suspected spinal level. CT is reserved for emergency situations, most commonly related to hydrocephalus and ventriculoperitoneal shunt malfunction. It is not used as a routine examination, due to concerns about ionizing radiation. Conventional radiography of the axial and appendicular skeleton usually is performed at diagnosis and includes dynamic radiography of the cervical spine with flexion and extension. Conclusion MPS is a group of inherited lysosomal storage disorders that may affect multiple organs and systems, including the CNS. A lysosomal enzyme deficiency leads to partially degraded GAG accu-

14 RG Volume 36 Number 5 Reichert et al 1461 Figure 16. MPS IIIB in a 12-year-old boy. Axial T2-weighted MR image of the brain shows thickening (arrows) of the diploe. Figure 17. MPS I in a 20-month-old boy. Sagittal contrast-enhanced T1-weighted MR image shows the typical appearance of a J-shaped sella turcica (arrows). Mega cisterna magna (*) also can be seen. Figure 19. MPS IIIC in a 10-year-old boy. Axial T2-weighted MR image of the brain shows mildly enlarged perivascular space (arrows) in the cerebral peduncles. Thickening (*) of the diploe is also seen. Figure 18. MPS II in a 10-year-old boy. Sagittal T2-weighted MR image of the cervical spine shows mega cisterna magna (black *). Although there is thickening of the soft tissue around C1 and C2 (white *), there is no sign of cord compression. mulation within lysosomes and in the extracellular space, inducing chronic degeneration of cells. There are distinct types of MPS, each defined by a mutated gene, a deficient enzyme, and storage of specific GAGs. CNS involvement is highly varied among different types of MPS, ranging from asymptomatic individuals to severely affected patients with motor and cognitive limitations. MR imaging is the method of choice to evaluate brain and spinal cord abnormalities. The differential diagnosis of MPS is limited, since the constellation of imaging findings is highly suggestive of the disease. For radiologists, especially neuroradiologists, it is important to be familiar with the main CNS manifestations of MPS. References 1. Clarke LA. The mucopolysaccharidoses: a success of molecular medicine. Expert Rev Mol Med 2008;10:e1 Accessed September 4, Giugliani R, Federhen A, Rojas MV, et al. Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment. Genet Mol Biol 2010;33(4): Muenzer J. Overview of the mucopolysaccharidoses. Rheumatology (Oxford) 2011;50(suppl 5):v4 v Barkovich AJ, Patay Z. Metabolic, toxic and inflammatory brain disorders. In: Barkovich AJ, Raybaud C, eds. Pediatric neuroimaging. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2012;

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