J Inherit Metab Dis (2011) 34:763–780

DOI 10.1007/s10545-011-9317-5

ORIGINAL ARTICLE

Brain and spine MRI features of Hunter disease: frequency,

natural evolution and response to therapy
Renzo Manara & Elena Priante & Marco Grimaldi & Lucia Santoro & Luca Astarita &
Rita Barone & Daniela Concolino & Maja Di Rocco & Maria Alice Donati &
Simona Fecarotta & Anna Ficcadenti & Agata Fiumara & Francesca Furlan &
Irene Giovannini & Franco Lilliu & Rodica Mardari & Gabriele Polonara &
Elena Procopio & Angelica Rampazzo & Andrea Rossi & Graziolina Sanna &
Rossella Parini & Maurizio Scarpa

Received: 18 December 2010 / Revised: 8 March 2011 / Accepted: 9 March 2011 / Published online: 5 April 2011
# SSIEM and Springer 2011

Abstract evolution and the impact of intravenous enzymatic replace-

Backgroud Hunter disease is a rare X-linked mucopolysac- ment therapy (ERT).
charidosis. Despite frequent neurological involvement, Methods Sixty nine brain MRI examinations of 36 Italian
characterizing the severe phenotype, neuroimaging studies patients (mean-age 10.4 years; age-range 2.2-30.8; severe
are scarce. phenotype in 22 patients) were evaluated. Twenty patients
Objectives To determine frequency and severity of neuro- had multiple MRIs (median follow-up 3.1 years, range
radiological mucopolysaccharidosis-related features; to cor- 1–16.9): among them 15 had MRIs before and after ERT,
relate them with clinical phenotype; to evaluate their natural six had repeated MRIs without being on ERT and five
while on ERT. Perivascular, subarachnoid and ventricle
Communicated by: Ed Wraith space enlargement, white matter abnormality (WMA)
Competing interest: None declared. burden, pituitary sella/skull/posterior fossa abnormalities,
periodontoid thickening, spinal stenosis, dens hypoplasia,
Dr. M. Ermani, (Neurology Department, University Hospital of
Padua) performed the statistical analysis.
R. Manara (*) : R. Mardari R. Barone : A. Fiumara
Neuroradiologic Unit, University Hospital of Padua, Referral centre for inherited metabolic diseases,
via Giustiniani 2, Department of Pediatrics, University of Catania,
35128 Padova, Italy Catania, Italy
e-mail: [email protected]
D. Concolino
E. Priante : I. Giovannini : A. Rampazzo : M. Scarpa Department of Pediatrics,
Centre for Rare Diseases, Department of Pediatrics, Magna Graecia University of Catanzaro,
University of Padua, Catanzaro, Italy
Padua, Italy
M. Di Rocco
M. Grimaldi Unit of Rare Diseases, Department of Pediatrics,
Neuroradiology Section, Department of Radiology, Gaslini Institute Genoa,
San Gerardo Hospital, Genova, Italy
Monza, Italy
M. A. Donati : E. Procopio
L. Santoro : A. Ficcadenti Metabolic and Neuromuscular Unit, Meyer Children Hospital,
Metabolic diseases, Institute of Maternal-Infantile Sciences, University of Florence,
Polytechnic University of Marche, Florence, Italy
Ancona, Italy
F. Furlan : R. Parini
L. Astarita : S. Fecarotta Rare Metabolic Diseases Unit Fondazione Mariani,
Department of Pediatrics, Federico II University, Pediatric Department, San Gerardo Hospital,
Naples, Italy Monza, Italy
764 J Inherit Metab Dis (2011) 34:763–780

myelopathy, vertebral and intervertebral disc abnormalities 2 and 4 years of age, the neurological involvement is
were graded by means of dedicated scales. progressive and death usually occurs in the first or second
Results Perivascular spaces enlargement (89%), WMAs decade. In the attenuated form clinical signs and symptoms
(97%), subarachnoid space enlargement (83%), IIIrd- have a slightly later onset, neurological deficit is minimal or
ventricle dilatation (100%), pituitary sella abnormalities even absent and patients may survive till late adulthood
(80%), cranial hyperostosis (19%), craniosynostosis (19%), (Martin et al. 2008).
enlarged cisterna magna (39%), dens hypoplasia (66%), Until recently, therapy for Hunter disease has been
periodontoid thickening (94%), spinal stenosis (46%), palliative. In 2006 the Food and Drug Administration has
platyspondylia (84%) and disc abnormalities (79%) were approved intravenous Enzyme Replacement Therapy
frequently detected. WMAs, IIIrd-ventricle dilatation and (ERT) with recombinant human iduronate-2-sulphatase
hyperostosis correlated with the severe phenotype (p< (idursulfase; Elaprase, Shire Human Genetic Therapies,
0.05). Subarachnoid spaces and ventricle enlargement, Cambridge, MA, USA), which had been shown to
WMAs and spinal stenosis progressed despite ERT, while improve many of the signs and symptoms as well as
other MR features showed minimal or no changes. the general wellbeing of patients with Hunter disease
Conclusions The spectrum of brain and spine MRI abnor- (Wraith et al. 2008). The true impact of idursulfase
malities in Hunter disease is extremely wide and requires a therapy on the Central Nervous System (CNS) manifes-
thorough evaluation. WMAs, atrophy/communicating hy- tations is however still debated and data are scarce.
drocephalus and spinal stenosis progress over time and The complex multisystem involvement of Hunter
might represent possible disease severity markers for new patients requires a multidisciplinary management and
treatment efficacy assessment. follow up (Wraith et al. 2008). This will include the
neuroimaging since CNS involvement needs to be early
diagnosed and strictly monitored, especially to prevent
Introduction communicating hydrocephalus- or spinal stenosis-related
consequences. Magnetic Resonance Imaging (MRI) repre-
Mucopolysaccharidoses (MPS) comprise a heterogeneous sents undoubtedly the most sensitive method to detect brain
group of rare recessive lysosomal storage diseases all and spinal abnormalities in mucopolysaccharidosis (Faerber
caused by impaired lysosomal glycosaminoglycans and Poussaint 2002). Several MRI findings have been so
(GAG) catabolism. Hunter disease (MPS type II, far described in Hunter patients but all the evidence is
OMIM#309900) is characterized by X-linked inheritance based on case reports and small and heterogeneous MPS
and is caused by mutations of the gene encoding cohorts (Lee et al. 1993; Parsons et al. 1996; Seto et al.
iduronate-2-sulphatase. The accumulation of the upstream 2001; Matheus et al. 2004; Müller-Forell et al., 2007;
metabolites (heparan and dermatan sulphate) within a variety Vedolin et al. 2007a and b, Finn et al. 2008). Actually, we
of cells, tissues and organs is responsible for progressive lack systematic neuroimaging studies including data on
multisystemic involvement. frequency and evolution of specific MRI abnormalities as
Clinical manifestations include typical facial dysmor- well as their correlation with the clinical phenotype.
phism and skeletal deformities, severe airway obstruction, Furthermore, the nature of these alterations is still debated
cardiomyopathy, organomegaly, joint stiffness and, in most and most of the physiopathological hypotheses, that have
patients, neurological decline. According to the phenotypic been thoroughly proposed (Lee et al. 1993; Parsons et al.
expression, patients are traditionally divided into two 1996; Seto et al. 2001; Matheus et al. 2004; Vedolin et al.
groups. In the severe form, clinical features appear between 2007a and b; Finn et al. 2008; Wraith et al. 2008) do not
explain the observed neuroradiological findings. Finally, it
is undetermined which features are merely markers of the
F. Lilliu : G. Sanna
disease and which might be used for establishing the
Department of Biomedical Sciences and Biotechnologies, efficacy of newly introduced therapies.
Cagliari, Italy This cross-sectional and longitudinal retrospective
study reports on cerebral and spinal MRI features in a
G. Polonara
Radiology Section, Department of Clinical Sciences,
large Italian group of Hunter patients in order to 1)
Polytechnic University of Marche, define their frequency and correlation with the clinical
Ancona, Italy phenotype, 2) delineate their natural course as well as the
impact of ERT; 3) be able to hypothesise on potential
A. Rossi
Pediatric Neuroradiology Department,
physiopathological mechanisms and 4) identify which
G. Gaslini Children’s Hospital, MRI features might be used to ascertain efficacy of
Genoa, Italy potential new therapies.
J Inherit Metab Dis (2011) 34:763–780 765

Patients and methods The following MRI features were scored:

– enlargement of Virchow-Robin perivascular spaces (PVSs)
We enrolled 36 Italian patients affected by Hunter disease (35
separately in corpus callosum and supratentorial white
males and 1 female, age range 2.8-32.2 years, mean age
matter according to Lee (Lee et al. 1993). A sieve-like
12.6 years). The diagnosis was made by urinary glycosamino-
appearance of supratentorial white matter was scored as 4
glycans measurements followed by demonstrating a deficient
(Fig. 1).
activity of iduronate-2-sulphatase in cultured fibroblasts or in
– white matter abnormality (WMA) burden in T2 weighted
leukocytes. Multiple sulphatase deficiency was excluded by
and Fluid Attenuated Inversion Recovery images (Fig. 2).
detection of normal activity of other lysosomial sulphatases.
– enlargement of subarachnoid cerebro-spinal fluid (CSF)
The phenotype was judged as “attenuated” in 14 (age
spaces according to Lee (Lee et al. 1993) (Fig. 3).
range 4.6-32.2 years; mean age 15.9 years) and “severe” in
– enlargement of IIIrd ventricle according to Lee (Lee et
22 patients (age range 2.8-20.1 years; mean age 10.5 years)
al. 1993) (Fig. 4).
by paediatricians expert in metabolic disorders according to
the classification recently published by Muenzer (Muenzer Enlargement of subarachnoid and ventricle CSF spaces
et al. 2009). Briefly, patients who presented with CNS were considered as markers of atrophy and or communi-
involvement, resulting in impaired cognitive abilities, cating hydrocephalus.
behavioural problems and neuropsychological developmen-
Skull and pituitary sella
tal delay or regression were judged to be affected by severe
phenotype, whereas patients who exhibited little or none
– cranial bones abnormalities, e.g. pituitary sella abnormal-
neurological involvement were considered “attenuated
ities (Fig. 5), cranial vault hyperostosis (Fig. 6a) as
phenotype”. Thirty-three patients received weekly infusions
proposed by Avrahami (Avrahami et al. 1987), craniosy-
of idursulfase (mean treatment duration 3.25 years, range
nostosis (scaphocephaly or trigonocephaly) (Fig. 6b) and
0.5-5.8 years); four subjects underwent bone marrow
platybasia as proposed by Koenisberg (Koenisberg et al.
transplantation; one patient had both treatments.
2005).
Two experienced neuroradiologists, blind to clinical
data, jointly evaluated retrospectively all brain and spine
MRI studies performed from 1991 to 2009. This included a Posterior fossa
total of 69 brain scans. Cervical spine studies were
available in 32 patients. All images had been acquired with – enlarged cisterna magna, small posterior fossa and
1.0T or 1.5T scanners and were judged of good quality, Chiari I malformation (Fig. 7).
despite the large time span considered. For 12 patients, the
neuroradiologists evaluated the images separately and inter-
Craniovertebral junction
observer reliability was calculated (Table 1).
Twenty patients had more than one MRI examination
– dens hypoplasia (only in subjects older than 2 years)
allowing longitudinal analysis (mean follow-up 4.1 years;
(Fig. 8)
median follow-up 3.1 years; range 1–16.9 years). Among
– atlanto-occipital assimilation
these patients, 15 subjects had MRI examinations before
– basilar invagination
and after ERT introduction (mean follow-up 3 years;
– characteristic soft tissue thickening around the odon-
median follow-up 2.4 years; range 1–8.7 years; mean
toid peg (measured from posterior cortical rim of the
follow-up after ERT beginning 1.7 years; range 1–
dens until the membrane tectoria) (Fig. 9);
2.9 years); six patients had multiple MRI examinations
– spinal stenosis according to the Space Available for the
without receiving ERT (mean follow-up 5.4 years; median
Cord (SAC) scale (Tierney et al. 2002) (Fig. 9). In
follow-up 2.5 years; range 1.2–17 years); three of them
particular the SAC was determined by subtracting the
eventually received ERT. Five patients had multiple
sagittal spinal-cord diameter from the corresponding
examinations while on ERT (mean follow-up 2.3 years;
sagittal spinal-canal diameter; a previous decompres-
median follow-up 2.0 years; range 1.5–3.6 years) .
sive surgery was scored as 5.
According to the available literature and our experience on
– mielopathy; syringomyelia was scored 3.
MRI abnormalities in mucopolysaccharidoses, we identified
several neuroradiological alterations, which were scored by
means of: 1) scales already present in literature (e.g. dilatation Spine
of IIIrd ventricle), 2) scales adapted to our study (e.g. spinal
stenosis) and 3) scales specifically created (e.g. intersomatic – cervical platyspondilia (in subjects older than 15 months)
disc abnormalities, white matter abnormality burden) (Table 1). (Fig. 10a)
766 J Inherit Metab Dis (2011) 34:763–780

Table 1 Scores of brain and spine MRI features used in the present study

MRI feature Scale

Enlargement of Virchow-Robin PVSs inside cor- 0 = none

pus callosum 1 = <10 PVSs with a diameter <3 mm
2 = >10 PVSs with a diameter <3 mm
3 = PVSs with a diameter of >3 mm
Enlargement of Virchow-Robin PVSs outside 0 = none
corpus callosum 1 = <10 PVSs with a diameter <3 mm
2 = >10 PVSs with a diameter <3 mm
3 = PVSs with a diameter of >3 mm
4 = sieve-like appearance of supratentorial white matter.
White matter signal abnormalities in T2-w and 0 = absent
FLAIR images 1 = mild
2 = moderate
3 = severe
Subarachnoid CSF spaces enlargement 0 = absent
1 = mild (widening of the sylvian and interhemispheric fissures <3 mm, but not all sulci are
involved)
2 = moderate (widening of all fissures and sulci between 3–5 mm with visualization of the
entire mesencephalic cistern)
3 = severe (widening of all fissures and sulci >5 mm with definite loss of cortex and white
matter)
IIIrd ventricle enlargement 0 = absent (<3 mm)
1 = mild (<5 mm but no temporal horn dilatation)
2 = moderate (<10 mm with temporal horn dilatation)
3 = severe (>10 mm)
Pituitary sella abnormalities (j-shaped, ω-shaped 0 = normal
or enlarged sella) 1 = present
Hyperostosis 0 = absent (<10 mm)
1 = present (>10 mm)
Craniosynostosis (scaphocephaly or 0 = absent
trigonocephaly) 1 = present
Platybasia 0 = absent (<125°)
1 = present (>125°)
Enlarged cisterna magna 0 = absent
1 = present
Chiari I malformation 0 = absent
1 = borderline (cerebellar tonsills herniation <5 mm)
2 = present (cerebellar tonsills herniation >5 mm)
Small posterior fossa 0 = absent
1 = present
Dens dysplasia 0 = absent
1 = mild (dysplasic dens reaching atlas arch)
2 = severe (dysplasic dens not reaching atlas arch)
Periodontoid tissue thickening 0 = normal (<4 mm)
1 = mild (<10 mm)
2 = severe (>10 mm)
Spinal stenosis 0 = normal (SAC 10.4-2.5 mm)
1 = mild stenosis (SAC 2.5-1 mm)
2 = severe stenosis (SAC <1 mm)
3 = mild cord compression (spinal cord diameter >5 mm)
J Inherit Metab Dis (2011) 34:763–780 767

Table 1 (continued)

MRI feature Scale

4 = severe cord compression (spinal cord diameter <5 mm)

5 = previous decompressive surgery
Myelopathy 0 = absent
1 = non-specific T2-hyperintensities
2 = T2-hyperintense lesion
3 = syringomyelia
Atlanto-occipital assimilation 0 = absent
1 = present
Basilar invagination 0 = absent
1 = present
Platyspondylia 0 = absent
1 = present
Other vertebral anomalies (schisis or vertebral 0 = absent
body fusion) 1 = present
Intervertebral disc abnormalities 0 = none
1 = reduction in height
2 = partially absence
3 = absence of intervertebral disc

PVSs: perivascular spaces; FLAIR: fluid attenuated inversion recovery; CSF: cerebro-spinal fluid; SAC: space available for the cord

– other vertebral anomalies, such as schisis or vertebral Statistical analysis

body fusion (Fig. 10c,d)
– intervertebral disc abnormalities (Fig. 10b). The variables with normal distribution were analysed using
the Student T test, while for variables not normally distributed
the Mann Whitney U test was used. Cathegorial variables
Frequency and severity of these abnormalities were were analysed using the Chi square of Pearson or the Fisher
determined with a cross-sectional analysis of our cohort; Exact test when required. The linear correlation was tested
when more than 1 MRI examination was available, the most using the Spearman Rho. Interobserver agreement was tested
recent examination was used (age range 2,2-30.8 years; mean by using the Kappa of Cohen coefficient. Significance level
age: 10,4 years). was set at p<0.05.

Fig. 1 Perivascular spaces

(PVSs) enlargement spectrum.
Bilateral enlarged PVSs in the
posterior region of centrum
semiovale, score 3 (a) and in the
basal ganglia and in juxta-
cortical regions, score 3 (b);
giant PVS in the right lenticular
nucleus, score 3 (c); typical
enlarged PVSs in the corpus
callosum, score 3 (d); sieve-like
appearance of the posterior part
of cerebral hemispheres, score 4
(e); enlarged PVSs in the mid-
brain (f and g)
768 J Inherit Metab Dis (2011) 34:763–780

Fig. 2 White matter signal abnormality spectrum. T2w axial images at the level of lateral ventricles showing minimal/absent, score 0 (a), mild (<1/3,
score 1) (b), moderate (<2/3, score 2) (c) and severe (>2/3, score 3) (d) supratentorial white matter involvement

Patient consent the other hand, we found a direct correlation between age and
periodontoid thickening (p=0.047, Spearman’s Rho test) and a
Written informed consent was obtained from all patients inverse correlation between age and sella abnormalities (p<
(or guardians of patients) participating in the study. 0.005, Student t-test) and dens hypoplasia (p<0.0005, Student
t-test).
The extent of WMAs (p=0.016, Mann-Whitney test), IIIrd
Results ventricle enlargement (p=0.0005, Mann-Whitney test) and the
presence of occipital hyperostosis (p=0.019, Chi-square test)
Cross-sectional analysis correlated with a severe phenotype while the presence of an
enlarged cisterna magna was more frequent in patients with
Frequency and severity of brain and spine MRI features are attenuated phenotype (p=0.016, Chi-square test).
shown in Table 2. MRI findings of patients who underwent bone marrow
Among pituitary abnormalities, four patients had a marked transplantation did not significantly differ from the whole
enlargement of the sella regardless of the severity of ventricular group of Hunter patients.
and subarachnoid enlargement. The presence of an enlarged
cisterna magna did not correlate with the presence and the Longitudinal analysis
severity of enlargement of supratentorial CSF spaces (either
ventricle [p=0,58, Mann-Whitney test] or subarachnoid spaces Table 3 reports MRI changes between first and last MRI
[p=0.41, Mann-Whitney test]). Regarding the craniovertebral examinations of all 20 patients with an MRI follow-up.
junction no association was found between dens hypoplasia Table 4 summarizes MRI changes in those 15 patients
severity and the presence of periodontoid thickening or spinal with an MRI examination shortly before and after ERT
stenosis (p=0.31 and p=0.68 respectively, Chi-square test). On introduction, while Table 5 compares MRI changes without

Fig. 3 Atrophy/communicating
hydrocephalus in 3 patients with
severe phenotype. Marked CSF
spaces enlargement with promi-
nent involvement of subarach-
noid (a) ventricular (b) or both
(c) compartments
J Inherit Metab Dis (2011) 34:763–780 769

Fig. 4 Atrophy/communicating
hydrocephalus spectrum at level
of the IIIrd ventricle Mild, score
1 (a) and severe, score 3 (b)
enlargement of IIIrd ventricle

ERT (6 patients) with MRI changes during ERT (5 Cranial vault hyperostosis and periodontoid thicken-
patients). ing progression was observed during the follow-up of
WMAs, subarachnoid CSF spaces and IIIrd ventricle patients not receiving ERT but comparison with other
enlargement worsened in several cases, though these MRI groups did not reach statistical significance (Fisher’s
features were graded at maximum score at the first exact test).
examination in 5/19, 5/19 and 7/19 subjects, respectively. PVSs enlargement score changes were seldom observed,
These changes were observed regardless of ERT introduc- likely due to different positioning of slices in follow-up
tion (Fisher’s exact test). examinations, without significant differences among groups
Also spinal stenosis at cranio-vertebral junction showed (Chi-square test).
a comparable worsening in the whole group and in those In few cases dens hypoplasia and pituitary sella
patients examined before/after ERT introduction, without or abnormalities showed an amelioration regardless of ERT
while on ERT (Fisher’s exact test). (Chi-square test and Fisher’s exact test, respectively).

Fig. 5 Pituitary sella abnormal-

ity spectrum. Magnification has
been kept relatively constant in
order to show size differences
(the brainstem is similar in all
images): typical J-shaped (a)
or ω-shaped (b) pituitary sella;
small sella in a hyperostotic
sphenoid bone (c); enlarged
sella with slight prolapse of the
optic chiasm (d)
770 J Inherit Metab Dis (2011) 34:763–780

Fig. 6 Cranial vault bone abnor-

malities. Thecal hyperostosis (a);
craniosynostosis with dolicho-
cephaly (b)

Discussion Enlargement of Virchow-Robin perivascular spaces (PVSs)

Hunter disease is one of the MPS in which the CNS is Virchow-Robin PVSs enlargement is a known but non-
primarily involved. This is the first large study aimed at specific feature of MPS since it has also been detected in a
determining frequency and evolution of known MPS-related number of different conditions such as myotonic dystrophy,
MRI features in Hunter disease. neurosarcoidosis, parkinsonism, chronic alcoholism and in

Fig. 7 Posterior fossa abnormality spectrum. Magnification has been space is visible below the cerebellar vermis (b); giant posterior fossa with
kept relatively constant in order to show posterior fossa differences in size megacisterna magna (c); megacisterna magna with dural sepimentation
(the brainstem is similar in all images): small posterior fossa with and relative cerebellar hypoplasia on coronal images (d, e); Chiari 1
impingement of neural structures (a); medium-sized posterior fossa with malformation with cerebellar tonsils below the foramen magnum (f)
modest impingement of cerebellar tonsils in the foramen magnum; CSF
J Inherit Metab Dis (2011) 34:763–780 771

Fig. 8 Dens hypoplasia spectrum. Normal finding with a well recognizable dens, score 0 (a); mild dens hypoplasia with the odontoid process reaching
the anterior arch of the atlas, score 1 (b); severe dens hypoplasia, score 2 (c); normal dens with severe spinal canal stenosis (d)

healthy subjects, as well. PVSs in healthy subjects tend to callosum. Nonetheless, no correlation was found between
increase in number and size with age, however, in contrast the clinical phenotype and the size and location of
to PVSs in MPS, they rarely involve the corpus callosum Virchow-Robin PVSs since they were massively present
(Groeschel et al. 2006). At present, the rare available neuro- also in the attenuated form as demonstrated in our series as
pathologic reports do not clarify the pathophysiologic well as in the literature (Shimoda-Matsubayashi et al. 1990;
mechanisms leading to enlarged PVSs. It is unclear whether Parsons et al. 1996; Shinomiya et al. 1996). In contrast to
PVSs enlargement is due to the storage of GAG around the previous studies which suggested a reduction (Lee et al.
vessels (Parsons et al. 1996) or to hampered liquid 1993) or an increase (Parsons et al. 1996) of the PVSs
reabsorption caused by deposits of mucopolysaccharides enlargement, in our study age did not correlate with the
in the leptomeninges (Matheus et al. 2004). Both mecha- severity of PVSs enlargement. Furthermore, during follow-up
nisms are supposed to lead to a progressive enlargement of only limited changes in PVSs were observed. Indeed, a slight
PVSs thus giving a “sieve-like” aspect in the late phases of worsening was detected in three out of 18 patients while a
disease (Matheus et al. 2004). slight improvement was found in two patients. These changes,
Our data confirm that the PVSs enlargement is frequent however, might be due to different slice positioning. There-
in Hunter disease, since more than 90% of patients fore, our data strongly suggests that PVSs do not significantly
presented these findings, especially at the level of corpus evolve in Hunter disease.

Fig. 9 Atlo-occipital junction and spectrum of spinal canal stenosis (b), severe stenosis with reduced CSF spaces (<1 mm, score 2) (c) and
due to periodontoid thickening. Normal sized spinal canal, score 0 (a), mild spinal cord compression with absent CSF spaces and reduced
mild stenosis with reduced CSF perimidollar space (<2.5 mm, score 1) spinal cord sagittal diameter, score 3 (d)
772 J Inherit Metab Dis (2011) 34:763–780

Fig. 10 Spine abnormalities.

Typical platyspondylia with
bullet-shaped vertebral bodies
(a); intervertebral discs with
reduced height in their central
part due to nucleus pulposus
hypotrophy, score 1 (b); anterior
arch schisis of the atlas in a
9-year-old boy which is more
visible on CT scan (c) than on
MRI (D); wedge-shaped L1
vertebral body (this deformity is
not rarely encountered at dorso-
lumbar level in MPS)

White matter signal abnormalities Atrophy and communicating hydrocephalus

WMAs are frequently observed in Hunter disease, partic- One of the most challenging aspect in Hunter disease
ularly in the periventricular regions. A combination of management is the differentiation between progressive
gliosis, loss of axon and myelin probably represents the brain atrophy and an incipient communicating hydroceph-
pathological substrate of these abnormalities (Lee et al. alus, which would require a prompt surgical intervention.
1993; Vedolin et al. 2007a and b), but direct pathological Both manifestations might share the same clinical and
findings are still lacking. instrumental findings. Firstly, the expected worsening of
Several visual semiquantitative scores of white matter signal neurological status in a patient with the severe phenotype,
abnormalities have been conceived for physiological ageing or which is often stepwise, might conceal the neurological
vascular dementia (Fazekas et al. 1987; Scheltens et al. 1993, deterioration due to hydrocephalus. Secondly, fundoscopy
Wahlund et al. 2001). No grading systems has been developed and visual evoked potential studies may be inconclusive
for evaluating WMAs in lysosomal storage diseases, where because of poor compliance and because chronic papil-
the white matter involvement is often diffuse and not clearly ledema may occur in Hunter patients even in the absence of
related to ischemia. Since most of our examinations were on increased intracranial pressure, probably due to deposition
films, we applied a semi-quantitative scale thus confirming a of GAG within the sclera (Beck and Cole 1984). Thirdly, in
primary supratentorial white matter involvement in Hunter both conditions CT and MRI examinations detect an
disease. The burden of WMAs was graded moderate or severe enlargement of subarachnoid and ventricular spaces. Final-
in nearly 75% of cases and directly correlated with the severe ly, neuroimaging cannot easily differentiate between
clinical phenotype. These findings, therefore, confirm the Hunter-related periventricular WMAs and transependimal
correlation between WMAs burden and the presence of leakage due to impaired CSF reabsorption in communicat-
cognitive impairment, already outlined in previous studies ing hydrocephalus. All the above may easily lead to a
(Vedolin et al. 2007a; Gabrielli et al. 2004). delayed or inappropriate surgical treatment.
J Inherit Metab Dis (2011) 34:763–780 773

Table 2 Frequency and severity of neuroradiological findings

0 1 2 3 4 n. a. Cohen’s K

Enlargement of Virchow-Robin PVSs inside CC 4/35 19/35 3/35 9/35 1 1

11% 54% 9% 26%
Enlargement of Virchow-Robin PVSs outside CC 6/36 5/36 5/36 18/36 2/36 1
17% 14% 14% 50% 5%
White matter signal abnormalities 1/35 8/35 12/35 14/35 1 0.71 (p=0.0002)
3% 23% 34% 40%
Subarachnoid CSF spaces enlargement 6/36 6/36 6/36 18/36 0.77 (p<0.0001)
17% 17% 17% 50%
IIIrd ventricle enlargement 0/36 5/36 13/36 18/36 0.74 (p<0.0001)
14% 36% 50%
Pituitary sella abnormalities 7/36 29/36 1
19% 80%
Hyperostosis 29/36 7/36 1
81 % 19 %
Craniosynostosis 29/36 7/36 1
81% 19%
Platybasia 36/36 0/36 1
100%
Enlarged cisterna magna 22/36 14/36 1
61% 39%
Chiari I malformation 34/36 1/36 1/36 1
94% 3% 3%
Small posterior fossa 33/36 3/36 1
92% 8%
Dens dysplasia 11/35 14/35 10/35 1 0.75 (p=0.0001)
31% 40% 29%
Periodontoid tissue thickening 2/35 31/35 2/35 1 1
6% 89% 6%
Spinal stenosis 19/35 9/35 4/35 3/35 1 0.85 (p<0.0001)
54% 26% 11% 9%
Myelopathy 34/35 0/35 0/35 1/35 1 1
97% 3%
Atlanto-occipital assimilation 36/36 0/36 1
100%
Basilar invagination 35/35 0/35 1 1
100%
Platyspondylia 5/32 27/32 4 1
16% 84%
Other vertebral anomalies 28/32 4/32 4 1
87% 12%
Intervertebral disc abnormalities 6/29 21/29 2/29 0/29 7 1
21% 72% 7%

n.a: not available; PVSs: perivascular spaces; CC: corpus callosum; CSF: cerebro-spinal fluid Cohen’s K: Cohen’s kappa coefficient
The score ranges from 0 (normal) to 1–4 according to the scale used for the evaluation . The thick vertical line discriminates between normal and
abnormal findings.
Missing data and Cohen’s K coefficient as a measure of Inter-observer agreement obtained from a sample of 12 patients are also reported.

Due to the difficulties in differentiating brain atrophy of the third ventricle while more than 80% showed an
from communicating hydrocephalus these conditions were enlargement of subarachnoid spaces. In as many as half of
considered together. In our series atrophy/communicating the cases they were graded severe. The clinical impact of
hydrocephalus was extremely frequent: with regard to their these features is still debated. Some authors have reported a
last MR examination all patients presented an enlargement correlation between severity of brain atrophy and cognitive
774 J Inherit Metab Dis (2011) 34:763–780

Table 3 MRI changes between

first and last MRI examinations Unchanged Worsened Improved Not available
in 20 patients. Mean follow-up
4.1 years; median follow-up Enlargement of Virchow-Robin PVSs inside CC 13**/18 3*/18 2/18 2
3.1 years; range 1–16.9 years Enlargement of Virchow-Robin PVSs outside CC 17**/19 1/19 1*/19 1
White matter signal abnormalities 12***/19 7/19 1
Subarachnoid CSF spaces enlargement 10*/19 9**/19 1
IIIrd ventricle enlargement 11*/19 8**/19 1
Pituitary sella abnormalities 18*/20 2**/20
Hyperostosis 17*/20 3**/20
Craniosynostosis 20***/20
Platybasia 16*/16 4**
Enlarged cisterna magna 19***/20 1/20
Chiari I malformation 20***/20
Small posterior fossa 20***/20
Dens dysplasia 16**/19 1/19 2*/19 1
Periodontoid tissue thickening 14**/18 3*/18 1/18 2
PVSs: perivascular spaces; CC: Spinal stenosis 13*/20 7**/20
corpus callosum; CSF: cerebro-
Myelopathy 17*/18 1°/18 2**
spinal fluid;
Atlanto-occipital assimilation 17**/17 3*
syringomyelia in Chiari I
malformation; Basilar invagination 20***/20
* indicates the number of patients Platyspondylia 15*/15 5**
who underwent bone marrow Other vertebral anomalies 14*/15 1/15 5**
transplantation (* one patient, ** Intervertebral disc abnormalities 12*/15 2/15 1/15 5**
two patients, *** three patients).

impairment in MPS (Vedolin et al. 2007a), while others did hamper venous blood outflow, thus leading to hydrocephalus
not find any association (Gabrielli et al. 2004; Barone et al. (Vedolin et al. 2007b). On the other hand, atrophy could be
1999). Our data showed a highly significant correlation caused by the progressive accumulation of GAG in blood
between the degree of third ventricle enlargement and the vessels, leading to ischemic damage and consequent neuro-
clinical phenotype. These findings are consistent with the nal death and gliosis (Lee et al. 1993). According to other
quantitative data published by Fan, who found the ventricle authors the direct intracellular storage of GAG is the cause of
enlargement as the sole direct parameter correlating with brain parenchyma disease, which determines atrophy and the
the presence of cognitive impairment (Fan et al. 2010). On ex-vacuo enlargement of CSF spaces (Parsons et al. 1996).
the other hand, we failed to detect a similar correlation In summary, subarachnoid and ventricle CSF enlarge-
between subarachnoid space enlargement and cognitive ment is a very frequent finding, its pathogenesis is still
impairment. The discrepancies between severe phenotype poorly understood and the lack of reliable diagnostic
and the two measurements (CSF enlargement of ventricles markers of communicating hydrocephalus necessitates
and subarachnoid spaces) might be due to the inadequacy further studies.
of the semiquantitative scores used for the subarachnoid
spaces enlargement. Sella dysplasia, cranial hyperostosis, craniosynostosis
Alternatively, the possible concomitance of the two
different conditions (i.e. diffuse enlargement of CSF spaces Pituitary sella abnormalities (“J” or “omega” shaped sella)
in atrophy and variable and unpredictable enlargement of have been widely documented in patients affected by MPS
subarachnoid spaces in communicating hydrocephalus) (Parsons et al. 1996). Our data confirm that the sellar region
might have interfered with the correlation, acting as a is characteristically affected in Hunter disease as a j-shaped
confounding factor. sella was found in more than 70% of patients and 4 subjects
The pathogenesis of cerebral atrophy/communicating showed a significant enlargement of the sella turcica. The
hydrocephalus is controversial. According to some authors latter feature did not correlate with the presence of severe
the communicating hydrocephalus is determined by an hydrocephalus and can therefore not be considered as a
impaired CSF reabsorption due to deposits of GAG in the marker of increased intracranial pressure.
Pacchionian granulations (Matheus et al. 2004). Other authors Differently from sella abnormalities, cranial hyperostosis
postulated that abnormal morphology of the skull base may is not considered a neuroradiological feature of Hunter
J Inherit Metab Dis (2011) 34:763–780 775

Table 4 MRI changes in 15

patients examined before and Unchanged Worsened Improved Not available
after enzyme replacement thera-
py introduction (one patient also Enlargement of Virchow-Robin PVSs inside CC 9/13 3/13 1*/13 2
underwent bone marrow trans- Enlargement of Virchow-Robin PVSs outside CC 13*/14 1/14 1
plantation) (median follow-up White matter signal abnormalities 8*/14 6/14 1
2.4 years; range 1–8.7 years;
median follow-up after ERT Subarachnoid CSF spaces enlargement 8*/14 6/14 1
beginning 1.6 years; range IIIrd ventricle enlargement 7*/14 7/14 1
1–2.9 years) Pituitary sella abnormalities 15*/15
Hyperostosis 14*/15 1/15
Craniosynostosis 15*/15
Platybasia 14*/14 1
Enlarged cisterna magna 15*/15
Chiari I malformation 15*/15
Small posterior fossa 15*/15
Dens dysplasia 12*/14 1/14 1/14 1
Periodontoid tissue thickening 10*/13 2/13 1/13 2
Spinal stenosis 11*/15 4/15
Myelopathy 14*/15 1/15
Atlanto-occipital assimilation 13*/13 2
PVSs: perivascular spaces; CC:
corpus callosum, CSF: cerebro- Basilar invagination 15*/15
spinal fluid; Platyspondylia 12*/12 3
*indicates the patient who un- Other vertebral anomalies 12*/12 3
derwent bone marrow transplan- Intervertebral disc abnormalities 10*/12 2/12 3
tation and subsequently ERT.

disease. Nonetheless, according to the scale proposed by children affected by headache (Schwedt et al. 2006), thus
Avrahami (Avrahami et al. 1987), a cranial hyperostosis underlying the markedly increased prevalence of this
was detected in nearly 20% of subjects, mostly in the severe feature in Hunter disease (Parsons et al. 1996; Seto et al.
phenotype. Also craniosynostosis, namely scaphocephaly 2001). Even if the megacisterna magna can be considered
and trigonocephaly, was detected in about 20% of cases. an enlargement of subarachnoid spaces, no correlation was
These features appear to be more frequent in Hunter found between its presence and the enlargement of the
patients compared to the general population (Hockley et subarachnoid space and ventricles. Interestingly, its pres-
al. 1988). According to murine MPS I studies, accumulat- ence correlated with an attenuated phenotype, where
ing GAG in growing cartilage is thought to cause a bone atrophy and hydrocephalus are less common.
maturation defect characterized by impaired osteoclast Bejjani estimated the prevalence of Chiari I malforma-
activity and decreased cartilage reabsorption (Wilson et al. tion in the general population between 0.5% and 5%
2009). This may also explain the above mentioned skull (Bejjani 2001) while the prevalence of a small posterior
abnormalities. These features should therefore be consid- fossa in normal subjects has not been reported. The
ered as manifestations of the pathological process which pathophysiological mechanism that leads to posterior fossa
affects the whole skeletal system in MPS, as commonly abnormalities in Hunter disease is not known, nor is its
documented by X-ray examinations at level of claviculas, clinical consequence; in our cohort one patient presented
ribs and tibias (Martin et al. 2008). Chiari 1 malformation and subsequently developed an
extensive syringomyelia at the age of five. Longer follow up
Posterior fossa abnormalities studies may help to clarify their potential prognostic signif-
icance and possible complications such as syringomyelia or
Similarly to the pituitary region, the posterior fossa seems CSF reabsorption defects.
to be often involved in Hunter patients. A megacisterna
magna was detected in nearly 40% of patients, while Chiari Cranio-cervical junction abnormalities
I malformation or a small posterior fossa were detected in 6
and 8% of subjects, respectively. Several cranio-cervical junction abnormalities have been
Both abnormalities can be observed also in general described in MPS, such as dens displasia, atlanto-axial
population though with a lower frequency. In a recent study instability or subluxation, periodontoid tissue thickening,
a megacisterna magna has been found in 0.2% of 681 spinal stenosis and compressive cervical myelopathy (Finn
776 J Inherit Metab Dis (2011) 34:763–780

Table 5 MRI changes in 6 patients without ERT and in five patients on ERT

Unchanged Worsened Improved Not available

Gr. 1 Gr. 2 Gr. 1 Gr. 2 Gr. 1 Gr. 2 Gr. 1 Gr. 2

Enlargement of Virchow-Robin PVSs inside CC 6**/6 4/5 1/5

Enlargement of Virchow-Robin PVSs outside CC 4*/6 5/5 1/6 1*/6
White matter signal abnormalities 5**/6 3/5 1/6 2/5
Subarachnoid CSF spaces enlargement 2/6 3/5 4**/6 1/5 1/5
IIIrd ventricle enlargement 2/6 2/5 4**/6 3/5
Pituitary sella abnormalities 4/6 5/5 2**/6
Hyperostosis 4/6 5/5 2**/6
Craniosynostosis 6**/6 5/5
Platybasia 4/4 5/5 2**
Enlarged cisterna magna 6**/6 4/5 1/5
Chiari I malformation 6**/6 5/5
Small posterior fossa 6**/6 5/5
Dens dysplasia 5*/6 4/5 1*/6 1/5
Periodontoid tissue thickening 4*/6 5/5 2*/6
Spinal stenosis 4*/6 3/5 2*/6 2/5
Myelopathy 4/4 5/5 2**
Atlanto-occipital assimilation 5*/5 5/5 1*
Basilar invagination 6**/6 5/5
Platyspondylia 4/4 5/5 2**
Other vertebral anomalies 4/4 3/4 1/4 2** 1
Intervertebral disc abnormalities 4/4 2/4 1/4 1/4 2** 1

PVSs: perivascular spaces; CC: corpus callosum, CSF: cerebro-spinal fluid

* indicates the number of patients who underwent bone marrow transplantation (* one patient, ** two patients).
Gr.1: group 1 (six patients, median follow-up 2.5 years; range 1.2–17 years); Gr.2: group 2 (5 patients, median follow-up 2.0 years; range 1.5–3.6 years).

et al. 2008). These abnormalities represent a critical aspect completed at late infancy we cannot ascertain if dens peg
in MPS, since lesion or compression of neural structures at MR abnormalities in young subjects are due to a delayed
the bulbar-spine junction may lead to breathing centres maturation or to an irreversible defect. The inverse
sufferance. Quadriparesis and respiratory arrest by trivial correlation between age and the presence of dens hypopla-
cervical trauma have been reported in patients with pre- sia as well as the follow-up data (see below) seem to
existent spinal stenosis (Lipson 1977; Hite et al. 2000). suggest that this feature might improve over time.
Cervical stenosis might also cause urinary retention and Cranio-cervical junction abnormalities may be due to
sensory disturbances (Koyama et al. 1994; Al Sawaf et al. several pathogenic mechanism. Thickening of the dura and
2008). Cranio-cervical junction is thought to be less hypertrophy of the paraspinal ligaments are thought to be
severely affected in Hunter disease than in other forms of due to progressive storage of GAG (Young et al. 1980;
MPS, such as the Morquio (MPS IV) and Maroteaux-Lamy Taccone et al. 1993; O’Brien et al. 1997; Kachur and Del
(MPS VI) syndromes. However, decompression surgery has Maestro 2000; Seto et al. 2001). In addition, chronic
been reported also in Hunter patients (O’Brien et al. 1997). inflammation due to incomplete odontoid peg development
Although no patient had signal abnormalities due to spinal and concomitant atlanto-axial instability might cause a
cord compression, spinal stenosis was found in nearly half progressive thickening of periodontoid soft tissue (Stevens
of our cases, thus underscoring the need of a careful et al. 1991; Parsons et al. 1996; Hite et al. 2000).
examination of this region. Pathological specimens have revealed the prevalence of
Similarly, even if the odontoid process is reported to be fibrocartilaginous granulation tissue in the periodontoid
“well-formed” in most Hunter patients (Wraith et al. 2008), tissue of MPS IV (Stevens et al. 1991) while dural balloon
about 65% of our patients presented with dens hypoplasia . cells due to GAG abnormal storage have been found in
Since the ossification of the tip of the dens should be MPS VI (Young et al. 1980) No pathological findings are
J Inherit Metab Dis (2011) 34:763–780 777

Table 6 MRI sequence

and brain/spine MRI features MRI sequence Brain and spine MR features
best visualized with
Brain FLAIR axial images Enlargement of Virchow-Robin PVSs outside corpus callosum
White matter signal abnormalities
Subarachnoid CSF spaces enlargement
IIIrd ventricle enlargement
Hyperostosis
Craniosynostosis
Brain/cervical sagittal T1 Enlargement of Virchow-Robin PVSs inside corpus callosum
Pituitary sella abnormalities
Hyperostosis
Enlarged cisterna magna, Chiari I malformation, Small posterior fossa
Dens dysplasia
Periodontoid tissue thickening
Spinal stenosis
Platyspondylia
Brain/cervical sagittal T2 Enlargement of Virchow-Robin PVSs inside corpus callosum
Pituitary sella abnormalities
Hyperostosis
Enlarged cisterna magna, Chiari I malformation, Small posterior fossa
Dens dysplasia
Periodontoid tissue thickening
Spinal stenosis
PVSs: perivascular spaces; Myelopathy
FLAIR: Fluid Attenuated Inver- Platyspondylia
sion Recovery; CSF: Intervertebral disc abnormalities
cerebro-spinal

available in Hunter patients. In our study we did not find mostly depends on the superior and inferior cartilaginous
any correlation between the severity of dens hypoplasia and plates, platyspondylia is likely due to the effects of
the thickening measured at the odontoid peg. In fact, spinal deposition of GAG in the growing cartilage, which
cord compression was observed even without dens hypo- interferes with normal ossification processes, as proposed
plasia, thus revealing that atlanto-axial instability is not the for the pituitary and skull abnormalities. The involvement
sole determinant of the thickening at the odontoid peg (see of the cartilaginous plates might also explain the inter-
Fig 8d). On the other hand, ligamentous laxity is not somatic disc abnormalities, i.e. height reduction or partial
evaluated by standard MRI and a definitive conclusion absence, as observed in nearly 80% of patients.
might require specific evaluations of the atlanto-axial Vertebral and disk changes may result in gibbus
instability by plain flexion and extension cervical spine formation, shortness of the neck, and restricted mobility
radiographs. as well as in a reduced height.

Vertebral and disk alterations Time course of MR features

Multiple bone and joint involvement due to GAG deposits The longitudinal analysis revealed that brain atrophy and/or
in growing cartilage and connective tissue is a common communicating hydrocephalus and WMA burden were the
finding in Hunter disease. Spine is not exempt and brain MRI features soften showing progression during the
morphologic abnormalities of vertebral bodies and inter- course of the disease, especially in the severe phenotype
somatic discs are often seen on neuroradiological examina- (Fig 11). During a mean life-span of 4 years 9 out of 19
tions (Parsons et al. 1996). Eighty-five per cent of our patients had a further enlargement of subarachnoid spaces,
patients had platyspondylia with typical bullet shaped eight out of 19 showed a progression of third ventricle
vertebral bodies. This appearance is normal in children enlargement and seven out of 19 showed an increase of
until the age of 12–14 months. In Hunter disease it WMA burden. These brain MRI changes reflect the well
probably represents a halting of the normal maturation of known neurological deterioration. Notably, several severe
the vertebral body. Since the growth of vertebral body Hunter patients had, already at first examination, the
778 J Inherit Metab Dis (2011) 34:763–780

Fig. 11 MRI changes during

follow up. Dramatic ventricle
enlargement in a 3-year-old child
in 1-year span from score 2 to 3
(a); white matter signal abnor-
malities worsening from score 2
at the age of 20 months to score 3
at the age of 6 years (b)

highest obtainable scores for these abnormalities. There- or severity of atrophy (Vedolin et al. 2007a, b). The cross-
fore, these figures likely underestimate the real rate of sectional analysis of Hunter patients performed in our study
progression. In addition, a progression of MRI abnormal- also did not find correlation between age and WMAs and
ities was also observed in the attenuated phenotype, where atrophy/communicating hydrocephalus severity, even when
a neurological involvement was not to be expected. This patients were subgrouped according to the clinical pheno-
fact supports the opinion that a dichotomic classification in type. The contradiction between the longitudinal (progres-
“severe” and “mild” phenotypes is a gross simplification sion of the disease) and the cross-sectional (no correlation
(Wraith et al. 2008) and does not fit with a disease where with age) analyses seem to reveal that disease duration and
the clinical manifestations are distributed in a continuous clinical phenotype do not completely account for the above
spectrum. For this reason, a more detailed scoring system of mentioned abnormalities course and that other confounding
disease severity is probably needed in order to better represent factors might act on the MR phenotype. Delayed or
the complexity of the phenotype and the variations occurring impaired myelination, neuronal loss with atrophy and
during disease progression. wallerian axonal degeneration, ependymal or meningeal
Our findings allow some further considerations. Accord- barrier dysfunction and increased intracranial pressure
ing to previous studies (Lee et al. 1993) WMAs are thought might concur to MRI white matter appearance and CSF
to appear subsequently to Virchow-Robin PVSs enlarge- enlargement spectrum thus likely hindering the effect of
ment. WMAs were found to progress during the follow-up disease duration.
in nearly half of our patients and showed an evolution Quantitative measurements of CSF enlargement and
which did not correlate with presence, severity and WMA burden or the use of new techniques such as
evolution of PVSs enlargement. Therefore, these two MRI diffusion tensor and magnetization transfer imaging might
features, even though both very common in Hunter disease, help to better understand the natural course of these MR
do present an independent course and likely recognize a features.
different pathogenesis. Among the extracerebral MR features we observed a
A recent large cross-sectional study on patients affected progression of occipital hyperostosis, periodontoid tissue
by different subtypes of MPS reported no correlation thickening and spinal stenosis in three out of 20, three out of
between disease duration and white matter abnormalities 19 and seven out of 20 patients, respectively. The latter
J Inherit Metab Dis (2011) 34:763–780 779

features further underscore the importance of a periodic in MPS. WMAs, atrophy and/or communicating hydro-
neuroradiological follow-up of the atlanto-occipital junction cephalus and cranial vault hyperostosis correlate with the
in order to plan a proper decompressive surgery, when needed. Hunter disease severe phenotype while an enlarged cisterna
Interestingly, we did not find any correlation between the magna is more frequent in the attenuated phenotype.
presence of dens hypoplasia and the progression of spinal ERT introduction does not seem to modify progression
stenosis, thus sustaining the hypothesis that the thickening of WMAs, atrophy/communicating hydrocephalus and
at the odontoid peg is not determined exclusively by the spinal stenosis, even though data are very preliminary and
presence of atlanto-axial instability. Moreover, dens hypo- a longer follow-up is needed. Therefore, these features have
plasia may improve over time, so that this feature should to be strictly monitored both in routine practise and when
not be regarded as an unfavorable prognostic factor for the evaluating new therapies response. A thorough evaluation
development of spinal stenosis. of MRI exams, especially if performed in a centralized
system, will increase the knowledge of the natural and post-
ERT effects in Hunter disease treatment course of the CNS involvement in Hunter patients
and will help outline the differences from other forms of
ERT has proven to be effective in Hunter patients in terms of MPS. A scale that considers WMAs, atrophy/communicat-
organomegaly and joint stiffness reduction and in improving ing hydrocephalus, dens hypoplasia, periodontoid tissue
quality of life (Wraith et al. 2008). Despite encouraging results thickening, spinal stenosis and myelopathy might be a valid
reported on two Hunter patients (Wang et al. 2009), the CNS tool for monitoring Hunter patients, while other MR
does not seem to benefit significantly from intravenous features seem to be less useful.
enzyme administration likely because the enzyme does not
pass the blood-brain barrier (BBB) (Al Sawaf et al. 2008). Acknowledgment We acknowledge Fondazione Pierfranco e Luisa
Mariani for their consistent economic support to the metabolic Center
Even if our data are preliminary and based on few patients,
in Monza.
neuroradiological features seem to respond poorly to the We acknowledge Frits Wijburg and Chiara Briani for their critical
treatment since brain MRI features seem to worsen despite support.
ERT introduction. Interestingly, even those tissues (e.g.
pituitary sella, Virchow-Robin PVSs, periodontoid thicken-
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