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Patterns of Brain Iron
Accumulation
Luís Antônio Tobaru Tibana
Nitamar Abdala
Leonardo Modesti Vedolin
Rene Leandro Rivero
Renato Adam Mendonça
Emerson Leandro Gasparetto
Ernesto Duarte Alves
Felipe Torres Pacheco
Matheus Luis de Souza Silva
Danilo Manuel Cerqueira Costa
Alda Tiaki Sato Tibana
Objective
The paper presents a new algorithim to
evaluate brain iron accumulation in MRI,
crystallizing current concepts in radiological
practice.
Introduction
Intracranial iron accumulation can occur in several diseases, with the
involvement of the brain parenchyma (more common in the globus
pallidus), pial surface, choroid plexus and / or pituitary gland.
Iron accumulation appears as hypointense on T2-weighted imaging and
isointense on T1. T2*-weigheted imaging may accentuate the degree of
hypointensity (“blooming”).
Kruer M.C AJNR 2012; 33:407-14
The final etiological diagnosis of brain iron accumulation is done with
close clinical correlation. However, we are focusing in those conditions
which image pattern is distinct
Step 1 – Recognize the pattern
Which structures are involved?
Distinguish the iron deposit in one of three patterns:
- Leptomeningeal
- Bone marrow, choroid plexus and pituitary gland
- Deep gray matter (globus pallidus)
First Step - Recognize the pattern
Superficial siderosis
Hemochromatosis
Hemosiderosis
Leptomeningeal
Bone marrow,
choroid plexus
and pituitary
gland
Deep gray
matter (globus
pallidus)
Neurodegeneration with brain iron accumulation (NBIA)
Multiple sclerosis
Parkinsonian syndromes
Cortical dementias
Brain aging
Leptomeningeal
This is a specific pattern of a condition called superficial
siderosis (SS) and results from hemosiderin deposition in the
subpial layers of the brain and spinal cord, as a consequence of
recurrent and persistent bleeding into the subarachnoid space.
Kumar N AJNR 2010; 31:5-14
Accelerated ferritin synthesis in the Bergmann glia of the
cerebellum may account for preferential cerebellar involvement
Koeppen AH, J Neuropathol Exp Neurol 1988; 47: 249–70
The classic clinical presentation of SS includes ataxia, cerebellar
dysarthria and sensorineural hearing impairment
Fearnley JM, Brain 1995; 118: 1051–66
Axial T2-weighted brain MR images
from patients with SS show hemosiderin
deposition along the cerebellar folia and
around the midbrain
Sagittal T1-weighted brain MR image
from a patient with SS shows severe
cerebellar atrophy.
MR images from the same patient with SS demonstrate superiority
of the gradient-echo technique in detecting the characteristic T2 hypointensity
(blooming effect)
Bone marrow, choroid plexus and pituitary
gland
Primary or secundary hemochromatosis (patients with transfusiondependent b-thalassemia major) lead to intracranial iron accumulation
at sites outside the blood-brain barrier, which include the pituitary
gland, choroid plexus, pineal gland, and area postrema. The
involvement of this p’s is highly suggestive of primary or secundary
hemochromatosis. Another site that can be included as typical iron
deposit in hemochromatosis is bone marrow
Drayer B AJR 1986;147:103–10
Wahid S Lancet 2001;357:115
28-year-old woman with
transfusion-dependent b-thalassemia major.
Pituitary siderosis
Bone marrow siderosis
Sagittal T1-weighted
The bone marrow shows
markedly decreased
signal intensity
Coronal T2 - weighted
The anterior lobe of the pituitary
gland shows markedly decreased
signal intensity
28-year-old woman with
transfusion-dependent b-thalassemia major.
Axial T2* - weighted GRE
The choroid plexus shows
markedly decreased
signal intensity
Choroid plexus siderosis
Deep gray matter
Unlike the previously shown image patterns, iron accumulation in the
deep gray matter is usually not specific, being common in several
diseases and even in the normal aging brain. Iron deposition occurs in
multiple sclerosis, human immunodeficiency virus dementia, Freidrich
ataxia, Alzheimer and Parkinson diseases, though to a lesser degree
than that seen in NBIA.
Regardless of etiology, the globus pallidus is usually the most
involved region.
Although in most cases of NBIA, the image pattern is nonspecific with
the diagnosis being performed with clinical data and especially using
genetic analysis, sometimes it is possible to distinguish specific
subpatterns.
Kruer M.C AJNR 2012 33:407–14
For this image pattern (deep gray matter), apply Step 2
Step 2 - Deep gray matter
 If your case fit into one of the image patterns below, there is good specificity!
These five image patterns are distinct.
Iron deposits in the globus pallidus +
Eye of the tiger
Midbrain T1 hyperintensity
Linear hyperintensity of the medial medullary lamina (“Japanese eye of the tiger”)
Widespread homogeneous iron deposits in deep gray matter
Widespread heterogeneous iron deposits in deep gray matter
 If not, the diagnostic challenge continues, requiring a close correlation with clinical
data, laboratory tests and in many cases, genetic analysis.
Kruer M.C, Brain 2011;134(pt 4):947–58
Kruer M.C AJNR 2012 33:407–14
Amaral LLF J Neuroimaging 2014;00:1-13
Hogarth P Neurology 2013;80:268-275
“Eye of the tiger”
Pantothenate Kinase-Associated Neurodegeneration (PKAN) is
the most frequently encountered subtype of NBIA. Classic
PKAN begins in childhood.
The “eye of the tiger” sign is virtually pathognomonic of the
PKAN (mutation in PANK2) and may become more intensified
or may fade with time. This is characterized by a T2-weighted
hypointense globus pallidus with a central T2 hyperintensity.
Other forms of NBIA have been purported to exhibit an eye of
tiger but feature subtle differences in the appearance of the
globus pallidus lesion.
Kruer M.C, Brain 2011;134(pt 4):947–58
Kruer M.C AJNR 2012 33:407–14
Chang CL Brain Behav 2011;1:55-56
PKAN
Eye-of-the-tiger sign
Axial FLAIR and axial T2-weighted image demonstrates increased T2 signal
in the center of globus pallidus
Axial GRE image through the same level demonstrates hypointensity
secondary to iron deposition in the posterior and lateral aspect of globus pallidus
Midbrain T1 hyperintensity
Before named SENDA (Static encephalopathy of childhood with
neurodegeneration in adulthood) due to the clinical course, BetaPropeller Protein-Associated Neurodegeneration (BPAN) is now
known a X-linked NBIA subtype with an unusual pattern of
neurodegeneration.
The neuroimaging of BPAN is distinct. In addition to iron deposition
in the globus pallidus and substantia nigra, BPAN features T1
hyperintensity of the substantia nigra with a central band of
hypointensity.
Amaral LLF J Neuroimaging 2014;00:1-13
Kruer M.C AJNR 2012 33:407–14
BPAN
Axial T1-weighted demonstrates
hyperintensity of the substantia nigra
and cerebral peduncles with central
linear hypointensity
Axial GRE demonstrates hypointensity
secondary to iron deposition in the
substantia nigra and cerebral peduncles
Linear hyperintensity of the medial medullary
lamina (“Japanese eye of the tiger”)
Distinctive imaging abnormality of Mitochondrial Membrane ProteinAssociated Neurodegeneration (MPAN) is linear T2 hyperintensity
involving the medial medullary lamina between globus pallidus
(internal and external segments). This imaging finding is present in
about one-fifth of patients
MPAN is caused by mutations in the C19orf12 gene (autosomal
recessive)
Hogarth P Neurology 2013;80:268-275
Hartig M, Int Rev Neurobiol 2013;110:73-84
The “japanese eye-of-the-tiger sign”
Axial T2-weighted and axial GRE image demonstrates linear hyperintensisy
of the medial medullary lamina in the center of globus pallidus
The “japanese eye-of-the-tiger sign”
Coronal T2-weighted image demonstrates linear hyperintensity
of the medial medullary lamina in the center of globus pallidus. There is
also iron deposition in the substantia nigra
Widespread homogeneous iron deposits in
deep gray matter
In aceruloplasminemia (ACP), MR imaging demonstrates widespread
brain iron accumulation, predominantly involving caudate, putamen,
globus pallidus, thalamus, red nucleus, and dentate. This is similar to
what occurs in neuroferritinopathy but in contrast to most other forms
of NBIA.
ACP is an autosomal recessive disease caused by mutation of the
ceruloplasmin gene (CP), located on chromosome 3q
In ACP, the iron deposition is homogeneous and widespread in deep
gray matter
Amaral LLF J Neuroimaging 2014;00:1-13
Kruer M.C AJNR 2012 33:407–14
Aceruloplasminemia
Axial T2-weighted and axial GRE image demonstrates homogeneous iron
deposition in caudate, putamen, globus pallidus and thalamus
Widespread heterogeneous iron deposits in
deep gray matter
Neuroferritinopathy is the only subtype of NBIA inherited as an
autosomal dominant caused by mutations in the FTL gene (Huntington
disease phenocopy)
Distinct MRI findings in NFT demonstrate bilateral, cystic
degeneration and heterogeneous iron deposition involving caudate,
putamen, globus pallidus and thalamus
Kruer M.C AJNR 2012 33:407–14
Chinnery PF Brain 2007;130(pt 1):110 –19
Amaral LLF J Neuroimaging 2014;00:1-13
Courtesy of Lázaro L.F. Amaral
Axial T2-weighted and axial GRE image demonstrates cavitations in
putamen and globus pallidus, with heterogeneous iron
deposition