Original Paper Pediatr Neurosurg 2014–15;50:26–30 DOI: 10.1159/000371658

Received: March 19, 2014 Accepted after revision: December 16, 2014 Published online: February 25, 2015

Cervical Spine MRI Findings in Patients with Mucopolysaccharidosis Type II Zbigniew Żuber a Agnieszka Jurecka c, d Elżbieta Jurkiewicz e Beata Kieć-Wilk b Anna Tylki-Szymańska f a Department of Pediatrics, St. Louis Regional Children’s Hospital, and b Department of Metabolic Diseases, Medical College, Jagiellonian University, Cracow, c Department of Genetics, University of Gdańsk, Gdańsk, and Departments of d Medical Genetics, e Radiology, MR Unit, and f Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, Warsaw, Poland

Abstract Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (EC 3.1.6.13). The purpose of this report is to describe cervical spine magnetic resonance (MRI) findings in MPS II patients and to correlate them with clinical phenotype. Seven cervical spine MRI examinations from Polish MPS II patients (mean age 11.4 years, median age 8 years, range 5–30) were evaluated. Six patients were classified as neurological (85.7%) and 1 as attenuated (14.3%). Five patients were treated with idursulfase (range 110–260 weeks, mean 195, median 200), while 2 patients never received the treatment. The following features were assessed: periodontoid thickening, spinal stenosis, dens hypoplasia, myelopathy, and vertebral and intervertebral disc abnormalities. Mean age at evaluation was 11 years (range 5–30, median 8). Cervical spine MRI was abnormal in all the patients and the most frequent abnormalities found were dens hypoplasia (100%), periodontoid thickening (100%), disc abnormalities (100%) and spinal stenosis (43%). There was no clear correlation between MRI findings and patients’ phenotypes. © 2015 S. Karger AG, Basel

© 2015 S. Karger AG, Basel 1016–2291/15/0501–0026$39.50/0 E-Mail [email protected] www.karger.com/pne

Introduction

Mucopolysaccharidosis type II (MPS II, Hunter syndrome, OMIM No. 309900) is caused by the deficiency of the enzyme iduronate-2-sulfatase (EC 3.1.6.13) that is responsible for breaking down heparan and dermatan sulfate within the cells [1]. It is a rare and life-limiting X-linked recessive disorder that affects approximately 1 in 77,000 newborn boys [2, 3]. Girls are affected rarely [4]. MPS II is a disease with multiorgan and multisystem involvement that has a variable age of onset and a variable rate of progression. According to the phenotypic expression, patients are traditionally divided into two groups. In the severe (neuronopathic) form, clinical features appear between 2 and 4 years of age, the neurological involvement is progressive and death usually occurs in the second decade. In the attenuated (non-neuronopathic) form, clinical signs and symptoms have a slightly later onset, neurological deficit is minimal or absent and patients may survive till late adulthood [5]. The neurological manifestations of MPS II include central nervous system (brain and spine) and peripheral nerve involvement. Central nervous system involvement with neurocognitive regression is the hallmark of severe forms of MPS I and MPS II, along with the other neurological symptoms of the disease [6]. Compressive cervical Agnieszka Jurecka Department of Genetics University of Gdańsk ul. Wita Stwosza 59, PL–80-308 Gdańsk (Poland) E-Mail ajurecka @ gmail.com

Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/29/2015 8:03:01 PM

Key Words Enzyme replacement therapy · Mucopolysaccharidosis type II · Hunter syndrome · Spinal stenosis

Table 1. Patient characteristics (demographic, molecular characteristics and clinical phenotypes)

Patient

Current age, years

Age of diagnosis, years

Start of ERT, years

Total idursulfase exposure, weeks

Mutation

Phenotype

1 2 3 4 5 6 7

9.5 6.5 13 8 30 5 8

2 3 6.5 3 18 5 2

6 4 10 4 n.t. n.t. 3

165 110 200 240 n.t. n.t. 260

p.467C–G c.998C>T c.257C>T c.998C>T p.1034G–T n.d. c.950_951delCT

neurological neurological neurological neurological attenuated neurological neurological

n.d. = No data; n.t. = not treated.

myelopathy is a well-known life-threatening complication in MPS patients. Glycosaminoglycan accumulation in the growing cartilage results in dens dysplasia, atlantoaxial instability, and subsequent periodontoid fibrocartilaginous tissue deposition with upper cervical stenosis [4, 7]. Since central nervous system involvement needs to be early diagnosed and monitored, especially to prevent communicating hydrocephalus or spinal stenosis, neuroimaging studies are a very sensitive and useful tool. Currently, both hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) using idursulfase (recombinant human iduronate-2-sulfatase, Elaprase®, Shire Human Genetic Therapies, Inc., Lexington, Mass., USA) are available for MPS II. ERT for MPS II has been demonstrated to be effective for visceral organs and soft connective tissue involvement [8], but poor or no efficacy was observed for brain involvement because of poor penetration across the blood-brain barrier (BBB) [9, 10]. Poor efficacy has also been speculated towards hard connective tissues such as bone and heart valves because of poor vascularity [11, 12]. The objective of the present study was to describe cervical spine magnetic resonance (MRI) findings in MPS II patients and to correlate them with patients’ clinical phenotype.

Elaprase Treatment Five patients received weekly intravenous infusions of idursulfase (Elaprase) at a standard dose of 0.58 mg/kg. Imaging Technique The MR examinations of patients were performed at 1.5-tesla scanners. The cervical spinal canal and craniocervical junction were examined with the following sequences and images: sagittal T2-weighted (TR = 2,990–5,290 ms, TE = 88–135 ms) and sagittal T1-weighted (TR = 440–649 ms, TE = 9.4–11 ms) with 3-mm section thickness, FOV = 24 × 24 or 30 × 30 mm; axial T2-weighted (TR = 3,400–5,780 ms, TE = 73–83 ms) with slice thickness 3 mm and FOV = 16 × 20 or 21 × 21 mm. In some patients additional coronal T2-weighted images were obtained, TR/TE  = 3,050/104 ms, slice thickness 3 mm, FOV = 23 × 23 mm. All examinations were done without intravenous contrast agent. Imaging Evaluation The images were evaluated for the following features [10]: dens hypoplasia, atlanto-occipital assimilation, basilar invagination, periodontoid tissue thickening, spinal stenosis, myelopathy, and other vertebral anomalies. Ethical Considerations The protocol was approved by the human-subjects institutional review board at The Children’s Memorial Health Institute. Written informed consent had to be provided by the parents or legal guardians of patients participating in the study.

Patients and Methods Patients We enrolled 7 Polish patients affected by Hunter’s disease (all male, age range 5–30 years, mean age 11.4, median age 8). All patients enrolled in the study had to have a diagnosis of MPS II confirmed by the biochemical determination of iduronate-2-sulfatase deficiency in leukocytes and by molecular analysis.

Cervical Spine MRI Findings in MPS II

Patients The mean age at evaluation was 11 years (range 5–30, median 8). At evaluation, 5 out of 7 patients had been receiving ERT for a mean of 195 weeks (range 110–260, median 200). Seven patients (table 1) were born at term and received a diagnosis of MPS II at a mean age of 5.6 years (ranging Pediatr Neurosurg 2014–15;50:26–30 DOI: 10.1159/000371658

27

Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/29/2015 8:03:01 PM

Results

Table 2. Scores of spinal MRI features used in the present study

Patient

Age at exam, years

Dens dysplasia

Periodontoid tissue thickening

Spinal stenosis

Other vertebral anomalies

1 2 3 4 5 6 7

9.5 4.5 13 8 30 5 8

2 2 1/2 2 1 2 1

1 1 1 1 1 1 1

2 0 0 1 3 0 0

1 0/1 1 1 1 1 1

from 2 to 18 years, median 3 years). Five patients began ERT with idursulfase at a mean age of 5.4 years (range 3–10, median 4). All were Caucasian. Six patients were classified as neurological (85.7%) and 1 as attenuated (14.3%) according to the classification by Muenzer et al. [13]. Five out of 7 patients received weekly intravenous infusions of idursulfase for a mean of 195 weeks. All 5 patients completed at least 110 weeks of treatment. All patients were compliant with idursulfase treatment and the compliance with weekly infusions was 100%. All infusions were administered in hospital settings. Imaging Studies Abnormalities at the craniocervical junction were detected in all the patients (table 2, fig. 1–7). The most frequent abnormalities found were dens hypoplasia (100%), periodontoid thickening (100%), disc abnormalities (100%) and spinal stenosis (43%). There was increased retro-odontoid soft tissue that was an intermediate signal on the T1-weighted and low signal on the T2-weighted images. This was associated with mild to moderate degrees of canal stenosis in 3 cases and cord compression in 1 patient.

Discussion

Several craniocervical junction abnormalities have been described in MPS disorders, such as dens dysplasia, atlantoaxial instability or subluxation, periodontoid tissue thickening, spinal stenosis and compressive cervical 28

Pediatr Neurosurg 2014–15;50:26–30 DOI: 10.1159/000371658

myelopathy [14]. Spinal cord compression is one of the major clinical complications of MPS disorders, especially MPS I, II, IV and VI and most frequently occurs at the atlantoaxial joints [15, 16]. Storage of glycosaminoglycans in the dura mater and supporting ligaments, kyphoscoliosis, and cervical bony stenosis are thought to be the main causes of myelopathy in MPS I, II and VI patients [17, 18]. Compressive cervical myelopathy is a critical problem since the involvement of neural structures at the bulbar-spine junction may lead to central respiratory failure [10]. The craniocervical junction is thought to be less severely affected in Hunter disease than in other forms of MPS, such as MPS IV or MPS VI [10]. Our study of 7 MPS II patients evaluated through cervical spine MRI confirms it. Only the oldest patient had signal abnormalities due to spinal cord compression, however, spinal stenosis was found in nearly half of our cases, thus underscoring the need for a careful examination of this region. Similarly, the odontoid process is reported to be ‘wellformed’ in most patients with Hunter disease [8]. All our patients irrespective of age presented only with mild dens hypoplasia. Additionally, all our patients presented with abnormalities of vertebral bodies and intersomatic discs. MRI represents the most sensitive method to diagnose and monitor spinal abnormalities. Despite the fact that in MPS II patients the craniocervical junction is less affected, baseline/early cervical spine evaluation and regular neurological assessment should still be performed routinely in all MPS II patients by MRI and neurophysiological studies. Żuber/Jurecka/Jurkiewicz/Kieć-Wilk/ Tylki-Szymańska

Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/29/2015 8:03:01 PM

Dens dysplasia: 0 = absent, 1 = mild (dysplastic dens reaching atlas arch), 2 = severe (dysplastic dens not reaching atlas arch); periodontoid tissue thickening: 0 = normal (

Cervical spine MRI findings in patients with Mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulf...
197KB Sizes 3 Downloads 10 Views