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ORIGINAL COMMUNICATION
Transcranial sonography in pantothenate kinase-associatedneurodegeneration
Vladimir S. Kostic • Marina Svetel •
Milija Mijajlovic • Aleksandra Pavlovic •
Milica Jecmenica-Lukic • Dusan Kozic
Received: 11 August 2011 / Revised: 12 October 2011 / Accepted: 15 October 2011 / Published online: 5 November 2011
� Springer-Verlag 2011
Abstract After it was reported that increased tissue iron
concentrations were associated with increased echogenicity
of the substantia nigra (SN) obtained with transcranial
sonography (TCS) in animal and postmortem studies, our
goal was to use this method in a disorder characterized with
iron accumulation in human brain tissue. Therefore, mag-
netic resonance imaging (MRI) and TCS were conducted in
5 unrelated patients with pantothenate kinase-associated
neurodegeneration (PKAN), caused by PANK2 mutations.
All patients had an eye of the tiger sign. Hypointense
lesions on the T2-weighted MRI images were restricted to
the globus pallidus (GP) and SN. TCS also revealed
bilateral hyperechogenicity restricted to the LN and SN,
with normal DTV values. Both TCS and MRI studies in
PKAN patients are in accordance with the pathological
findings that accumulation of iron, even in advanced cases,
is restricted to the GP and SN, suggesting selective
involvement of these structures.
Keywords Transcranial sonography � Pantothenate
kinase-associated neurodegeneration
Introduction
From the first report of an abnormality on transcranial
sonography (TCS) that was specific for Parkinson’s disease
(PD) (i.e., hyperechogenicity of the substantia nigra (SN)
in up to 90% of patients with PD, but also in approximately
10% of the healthy subjects) [1–3], this technique has
gathered increasing attention in other degenerative disor-
ders, because it enabled studies of not only midbrain
structures, including echogenicity of the thalamus, lentic-
ular nucleus (LN), and caudate nucleus, but also the
transverse diameter of the third ventricle and of the frontal
horn of the lateral ventricle [4, 5]. The reason for hyper-
echogenicity of the SN in PD patients is not clear, although
several reports found an association between increased iron
content in the SN and its hyperechogenicity [6–10].
Neurodegeneration with brain iron accumulation
(NBIA) encompasses a group of progressive extrapyrami-
dal disorders [11], with the pantothenate kinase-associated
neurodegeneration (PKAN) as its major form (50–70% of
cases of NBIA), caused by a mutation in the PANK2 gene
[12].
Considering the proposed role of iron in SN hyperech-
ogenicity, we investigated TCS findings in five genetically
proven cases of PKAN, a disease characterized by brain
iron deposition.
Patients and methods
Five patients with PKAN from five unrelated, nonconsan-
guineous families with clinical presentation of extrapyra-
midal symptoms and signs and neuroimaging evidence of
iron deposition in the basal ganglia were included in the
study. PANK2 mutations were identified in all our patients,
V. S. Kostic (&) � M. Svetel � M. Mijajlovic � A. Pavlovic �M. Jecmenica-Lukic
School of Medicine, Institute of Neurology CCS,
University of Belgrade, Ul. Dr Subotica 6,
11000 Belgrade, Serbia
e-mail: [email protected]
D. Kozic
School of Medicine, MRI Center,
University of Novi Sad, Novi Sad, Serbia
123
J Neurol (2012) 259:959–964
DOI 10.1007/s00415-011-6294-4
as previously reported (Table 1) [13]. According to the
criteria of Hayflick et al. [11], only patient 4 (Table 1) had
‘‘classic’’, while the other 4 patients had an ‘‘atypical’’
form of the PKAN. Patients were clinically examined by
two independent neurologists (MS, VSK), and MRI scans
were analyzed by the same neuroradiologist (DK). The
study was approved by the Ethical Committee of the
School of Medicine University of Belgrade. After written
informed consent was obtained from the patients, detailed
clinical data were collected and TCS and MRI were con-
ducted on the same day.
TCS was performed (MM, who was blinded to the diag-
nosis and MRI findings) through the preauricular acoustic
bone windows using a color-coded phased-array ultrasound
system equipped with a 2.5 MHz transducer (ProSound
Alpha 10, Aloca, Japan). The ultrasound parameters chosen
were penetration depth of 16 cm, dynamic range 50–55 dB,
and high persistence. Image brightness, contrast, and time-
gain compensation were adjusted to obtain the best image.
Substantia nigra echogenic size measurements were per-
formed on axial TCS scans automatically after manually
encircling the outer circumference of the SN’s echogenic
area. According to the previously published criteria from our
laboratory [14], echogenic sizes of B0.19 cm2 were classi-
fied as normal, sizes of C0.25 cm2 as markedly hyperecho-
genic, and sizes in-between as moderately hyperechogenic.
Echogenicity of the lenticular nuclei, the heads of the cau-
date nuclei, and the thalami was classified as hyperechogenic
when it was more intense that the surrounding white matter
(classification was based on the more affected side). The
width of the third ventricle (DTV) was measured on a stan-
dardized diencephalic axial scanning plane and was deter-
mined by the minimum transverse diameter on axial TCS
scan (for details considering scanning planes see [15]).
Table 1 Demographic and clinical features of patients
Patient 1 2 3 4 5
Age (years) 29 37 38 16 35
Sex M F F M F
Age of disease onset (years) 18 25 20 10 13
Duration of the disease
(years)
11 12 18 6 22
Family history – – – – –
Consanguinity – – – – –
Mutation 1583C [ T
(T528M);
homozygous
1583C [ T
(T528M);
homozygous
1583C [ T
(T528M);
homozygous
1583C [ T
(T528M)/
1418del7
1583C [ T
(T528M)/
1418del7
Initial symptom(s) Lingual dystonia Speech disturbance Foor dystonia Oromandibular
dystonia
Oromandibular
dystonia
Dystonia ??? ?? ??? ??? ???
Oromandibulofaciolingual
dystonia
??? ?? ?? ??? ???
Chorea – – ? ? ?
Parkinsonism ? – ? ? ?
Cerebellar involvement – ? – – –
Gait disturbance ??? ? ?? ??? ???
Pyramidal involvement ?? ? ? ? –
Dysarthria ??? ?? ??? ??? ???
Dysphagia ??? ? ? ??? ??
Axial involvement ??? ? ?? ??? ??
Retinitis pigmentosa – – – ? –
Optic atrophy – – – ? –
Behavioral abnormalities ? ? ? ? ?
Cognitive impairment ? – ? ?? ?
Ocular movement disorders – – – – –
Apraxia of eyelid opening ? – – – –
Acanthocytosis – – – – –
Peripheral neuropathy – – – – –
? unknown or not examined, – not present, ? mild, ?? moderate, ??? severe
960 J Neurol (2012) 259:959–964
123
Results
Demographic and clinical features of our patients are pre-
sented in Table 1. The mean age was 31 years (range
16–38 years), with rather long duration of the disease
(mean: 13.8 years; range: 6–22 years). The PANK2 muta-
tion 1583C [ T (T528M) was found in 8 out of 10 alleles.
This missense mutation was identified as one of the most
frequent among PKAN patients [13]. Dystonic phenomena
were the presenting symptom in 4 patients (Table 1). At
the inclusion in the study, the most prominent symptoms
and signs included dystonia, particularly of the oro-
mandibulofaciolingual and axial distribution, with gait
disturbances, dysarthria, and dysphagia, and pyramidal
affection.
TCS revealed hyperechogenicity restricted to the LN
and SN with normal DTV values. Extensive hyperechog-
enicities of the lenticular nuclei (Table 2) were bilateral
and symmetrical, with the exception of patient 1 whose
echogenic area was larger in the right LN). Four patients
had marked, bilateral hyperechogenicity of the SN with the
exception of patient 3, where we detected unilateral,
moderate hyperechogenicity (0.20 cm2) of the right SN,
due to an insufficient acoustic bone window.
All our patients had an eye of the tiger sign (Table 2 and
Fig. 1). Hypointense lesions on the T2-weighted images
were in accord with the TCS data, being restricted to the
globus pallidus (GP) and SN. Only in patient 2 hypointense
were lesions of the dentate nuclei also observed.
Discussion
The main finding of our study is that the hyperechogenic
areas detected in the TCS study correlate with the hypo-
intense regions detected during MRI examinations. With
both techniques the observed changes are restricted to the
LN/GP and the SN, regions where, even in advanced cases,
the accumulation of iron selectively occurs in PKAN
(Fig. 1) [16].
In patients with PD, TCS detects hyperechogenicity of
the SN in up to 90% of patients [1–3]. Until recently, only
increased tissue iron concentration was associated with an
increased area of echogenicity of the SN in animal and
postmortem studies [6, 7, 10, 17, 18]. Animal experiments
revealed a dose-dependent increase in SN echogenicity
after the stereotactic injection of various concentrations of
iron into the SN [17]. Zecca et al. [18] scanned postmortem
brains from normal individuals and a found positive cor-
relation between the echogenic area of the SN and the
concentration of iron, H- and L-ferritins, the main iron
storage proteins, but a negative correlation between ech-
ogenicity size and neuromelanin content in the SN. How-
ever, increased iron concentration alone probably cannot be
an explanation for the observed SN hyperechogenicity in
PD patients, and other factors, such as iron-binding pro-
teins may also have a role [4]. Mutational analyses of the
ceruloplasmin (critically involved in iron transport across
the cell membranes) gene variations in PD showed that at
least two of them (D554E and R793H) may be associated
Table 2 Findings of transcranial brain sonography (TCS) and magnetic resonance imaging (MRI) studies
Patient 1 2 3 4 5
TCS
SN-r (echogenic size in cm2) 0.39 0.42 0.2 0.43 0.54
SN-l (echogenic size in cm2) 0.39 0.45 0.17 0.66 0.51
SN asymmetry index 1.13 1.07 1.17 1.53 1.06
NL-r (echogenic size in cm2) 2.11 0.8 0.83 0.48 0.9
NL-l (echogenic size in cm2) 0.86 0.8 0.87 0.56 0.92
NCa-r (echogenic size in cm2) – – – – –
NCa-l (echogenic size in cm2) – – – – –
Thalamic hyperechogenicity – – – – –
Hyperechogenicity of red nucleus – – – – –
Raphe hypoechogenicity ? – – ? ?
DTV (mm) 5 6 4 5 4
MRI
,,Tiger eye‘‘sign ??? ?? ??? ? ??
Globus pallidus hypointensity ??? ??? ??? ?? ??
SN hypointensity ?? ? ? ? ?
Nucleus dentatus hypointensity – ? – – –
r right, l left, SN substantia nigra, NL lenticular nucleus, Nca caudate nucleus, DTV diameter of the third ventricle, – absent, ? mild,
?? moderate, ??? marked, TCS transcranial brain sonography, MRI magnetic resonance imaging
J Neurol (2012) 259:959–964 961
123
with hyperechogenicity of the SN [8]. In addition to iron
content, Berg et al. [10] recently observed correlation of
SN echogenicity with the activation of microglia, known to
contain high amounts of ferritin.
We assumed that the proposed role of iron deposits in
the hyperechogenicity of distinct brain structures obtained
by TCS can be substantiated by the use of this method in
patients with disorders characterized with iron accumula-
tion in specific areas of the brain. Therefore, we studied
5 patients with genetically confirmed diagnosis of PKAN
(Table 1). Interestingly, a global increase in brain iron is
not seen in PKAN: instead, the accumulation of iron in
pathological studies is, even in advanced cases, rather
restricted to the GP and SN pars reticulata (SNr), sug-
gesting selective involvement of these structures [19].
Routine iron staining detects the metal mainly in the
microglia and macrophages, but also in scattered neurons
and extracellularly, around blood vessels [16]. In regions of
extensive iron deposition, axonal spheroid bodies, many
positive for iron, probably represent a consequence of the
defects in axonal transport or membrane integrity [20].
Pantothenate kinase is a regulator in the synthesis of free
fatty acids; therefore, it is not clear how defects in lipid
metabolism may cause iron deposition [20]. Schneider et al.
[21] suggested that even if iron deposition was not the initial
and causative factor, but rather an epiphenomenon of cell
degeneration, it probably had a perpetuating role in the
cascade of events following disease initiation. Indeed, it has
been shown that excess deposition of iron may cause neu-
ronal degeneration, gliosis, and spheroid formation [22].
MRI studies in PKAN are in accord with pathological
findings. The primary neuroimaging changes in PKAN due
Fig. 1 a T2-weighted MR image of the midbrain of patient with the
pantothenate kinase-associated neurodegeneration (PKAN), with
b sonographic images of corresponding midbrain axial sections,
showing hyperechogenicity of the SN. c Bilateral T2-weighted
images of the ‘‘eye of the tiger’’ sign, with d sonographic image of
corresponding region (arrow shows hyperechogenicity of the lentic-
ular nucleus)
962 J Neurol (2012) 259:959–964
123
to high iron in basal ganglia are hypointense lesions in the
GP and SNr on T2-weighted images [23–26]. In pre-
symptomatic patients the hyperintense lesions predomi-
nate, but with disease progression, the hypointensities
appear and eventually prevail [27]. In PKAN, the deposi-
tion image pattern of bilateral symmetrical hyperintense
signals surrounded by hypointensity on T2-weighted ima-
ges (i.e., eye of the tiger sign) is highly specific and almost
pathognomonic feature (Fig. 1) [11, 25]. The central
hyperintensity is probably due to axonal swelling with
spheroid formation, gliosis, and neuronal loss and degen-
eration, while the surrounding hypointensity represents
iron deposition [24].
As expected, all our patients have an eye of the tiger
sign, with T2-weighted hypointense lesions restricted to the
GP and SN (Table 2). Only one patient also had hypoin-
tensity of the dentate nuclei. McNeill et al. [25] used T2*
and T2 fast spin echo brain MRI and found that in most
PKAN cases abnormalities were also restricted to GP and
SN and that 100% had an eye of the tiger sign (subtle in
some mildly affected patients), while in a minority of cases
hypointensity was observed in the dentate nuclei.
In continuation, our TCS data (Table 2) revealed bilat-
eral extensive hyperechogenic areas in the region of the
lenticular nuclei and SN (Fig. 1). Unfortunately, it is not
possible to visualize the pars reticulata separately by TCS:
only the whole SN can be seen. According to criteria used
in this study, in one patient with mild symmetrical MRI
hypointensity of the SN (patient 3 in Table 2), TCS
detected only unilateral SN hyperechogenicitiy. Hayflick
et al. [28] described the late appearance of radiographic
evidence for iron deposition in the SNr in PKAN. But even
then, since MRI in our patient showed bilateral changes,
this MRI/TCS mismatch may be due to a lower sensitivity
of TCS in revealing iron deposits.
Two previous studies addressed the same issue [29, 30].
The autosomal-recessive Kufor-Rakeb syndrome, induced
by mutations in the ATP13A2 gene (PARK9 locus), is
associated with the presence of iron accumulation in the
basal ganglia, placing the syndrome among disorders of
NBIAA [29]. Bruggemann et al. [29] showed that, despite
of an association of single ATP13A2 heterozygous muta-
tions with parkinsonism, the SN had a normal appearance
on TCS in all mutation carriers. The authors explained the
lack of SN hyperechogenicity in such patients by the
‘‘putative presence of different iron compounds and bind-
ing partners’’. In another study, Liman et al. [30] performed
TCS in 6 patients with a diagnosis of NBIA with
(3 patients) and without (3 patients) PKAN mutation, and
in 1 patient who was not genetically tested, but had typical
eye of the tiger sign. All of them had significantly
increased size of SN hyperechogenicity, together with the
hyperechogenicity of the nucleus rubber in most of them.
However, contrary to our data, they did not observe any
changes in the GP when compared to controls, possibly due
to the heavy dystonic movements that made it difficult to
properly obtain signal abnormalities.
Our study of patients with PKAN showed that echoge-
nicity changes of brain tissue identified by the TCS cor-
relate with the MRI findings and closely follow
pathological changes characterized by iron accumulation.
Acknowledgments This study was supported by a grant from the
Ministry of Science and Technology, Republic of Serbia (project no.
175090). VSK had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis.
Conflict of interest The authors declare that they have no conflicts
of interest.
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