Introduction
Dentate nucleus is the largest of deep cerebellar nuclei. It has a predictable imaging
appearance with respect to the surrounding cerebellar white matter during the first
year of life. At term it is hypointense on T1 and hyperintense with a dark serrated
rim on T2. By 6 months of age, it remains slightly brighter on T2-weighted (T2W) images
and the hypointense rim cannot be separately distinguished from the surrounding cerebellar
white matter.[1] Therefore, increased signal in dentate nucleus on T2W or fluid-attenuated inversion
recovery (FLAIR) sequences beyond 6 months is abnormal. Diffusion restriction at any
age is abnormal.[2]
Numerous conditions can affect the dentate nuclei. A recent review [3] elucidated the clinico-radiological approach to aid the diagnosis and management
of these conditions. Careful assessment of the differential involvement of dentate
hilus, peridentate white matter, rest of the cerebellar white matter, cerebellar gray
matter and brainstem, and supratentorial abnormalities can help narrow down the possibilities.
We present a pictorial review of the various pathologies affecting dentate nuclei
and their imaging findings encountered in our institute.
Role of computed tomography
The role of computed tomography (CT) is well established in identifying the variety
of conditions known to cause calcifications in the dentate nuclei [Table 1].[4] If present, it narrows down the differential diagnosis in accordance with the age
at presentation, history, and clinical features.
Table 1
Causes of dentate nucleus calcification
|
Physiological
|
|
Age related
|
|
Congenital/hereditary disorders
|
|
Cockayne syndrome
|
|
Primary familial brain calcification/Fahr’s syndrome
|
|
Aicardi-Goutiere’s syndrome
|
|
Leukoencephalopathy with calcifications and cysts (LCC)
|
|
MELAS
|
|
Spinocerebellar ataxia type-20
|
|
Cerebrotendinous xanthomatosis
|
|
Endocrine
|
|
Hypothyroidism
|
|
Hypoparathyroidism
|
|
Hyperparathyroidism
|
|
Pseudohypoparathyroidism
|
|
Post-thyroidectomy
|
|
Others
|
|
Lead poisoning
|
|
Lupus erythrematosus
|
|
Hypoxic ischemic encephalopathy
|
Role of magnetic resonance imaging
For eliciting the subtle signal changes in the dentate with associated abnormalities
of the rest of the brain and spinal cord, magnetic resonance imaging (MRI) is the
investigation of choice. Sequences which are routinely acquired include T1, T2, susceptibility-weighted
imaging (SWI)/gradient echo (GRE), diffusion-weighted imaging (DWI) and postcontrast
T1W imaging.
Conditions affecting dentate nuclei and their imaging appearance
These conditions have been elaborately described by Van der Knaap [5].
Leukodystrophies
Krabbe’s disease or globoid cell leukodystrophy is an autosomal recessive disorder
caused by the deficiency of galactocerebroside β-galactosidase causing accumulation
of cerebroside in lysosomes of white matter forming characteristic globoid cells.
Subtypes include early infantile (most common), late infantile onset, juvenile, and
adolescent. CT plays an important role as bilateral hyperdense thalami are a characteristic
feature of this entity. MRI shows T2/FLAIR hyperintensity in the periventricular white
matter and occasionally optic nerve/chiasma hypertrophy. Dentate may be involved.
Postcontrast images may show nerve enhancement [Figure 1].
Figure 1 (A-D): Krabbe's disease - A 2-year-old girl presented with hyperirritability, hypertonia,
fever, and developmental regression with cognitive decline and nystagmus for the past
6 months. CT (not shown) showed bilateral hyperdense thalami. (A) Axial T2WI shows
symmetrical hyperintensity in bilateral dentate nuclei (white arrows), (B) with subtle signal changes in the posterior limb of internal capsules and (C)
corona radiata. (D) Coronal T2WI shows hypertrophy of the right half of optic chiasma
(white arrow). No postcontrast enhancement was noted in this case (not shown)
Alexander’s disease is a nonfamilial leukoencephalopathy presenting in, infantile,
juvenile, or adult forms. Most reported cases are infantile onset presenting with
global developmental delay. Characteristic MRI findings include extensive supratentorial
white matter hyperintensities with frontal predominance and involvement of subcortical
white matter. Signal changes are also noted in the basal ganglia. T1 hyperintense,
T2 hypointense capping is noted adjacent to the frontal horns bilaterally. Postcontrast
images reveal enhancement of the periventricular rim and the dentate nucleus [Figure 2].
Figure 2 (A-E): Alexander's disease - A 3-year-old boy presented with progressive behavioral disturbances
with hypertronia and abnormal gait for the past 1 year. (A) Axial T2WI shows hyperintensity
in the cerebellar white matter and dentate nuclei (white arrowhead); (B) extensive
supratentorial white matter hyperintensities are noted, with frontal predominance
and involvement of subcortical white matter. Capping is noted adjacent to the frontal
horns bilaterally, hypointense on T2 (B) (white arrow), and hyperintense on T1WI (C). Bilateral striatal atrophy with altered signal intensity
noted with associated dilatation of the lateral ventricles. (D and E) Axial T1 postcontrast
reveals enhancement of the dentate nucleus and peridentate cerebellar white matter
(white arrows) as well as the periventricular rim (white arrowheads)
Canavan’s disease or spongiform leukodystrophy is an autosomal recessive disorder
caused by the deficiency of N-acetylaspartylase (NAA). The condition is characterized
by early onset macrocephaly. MRI shows diffuse T2/FLAIR hyperintensity in the supratentorial
white matter. Globus pallidus is involved. Magnetic resonance spectroscopy (MRS) shows
a large NAA peak [Figure 3].
Figure 3 (A-C): Canavan's disease - An 8-month-old girl presented with hypotonia, cortical blindness,
and macrocephaly since 3 months of age. (A) Axial T2WI shows extensive hyperintense
signal changes in the supratentorial white matter with involvement of the subcortical
U-fibres. Patchy signal change is also noted in the globi pallidi (white arrows) and anterolateral thalami bilaterally. (B) Coronal T2WI shows similar signal changes
with involvement of the dentate hilus bilaterally (white arrows). (C) MRS at TE 135 ms from the basal ganglia shows large NAA peak at 2.02 ppm
Aicardi–Goutiere’s syndrome is an autosomal recessive disorder characterized by microcephaly,
chronic cerebrospinal fluid (CSF) lymphocytosis, and raised levels of CSF interferon-α.
Onset is typically in the first year of life with feeding difficulties, low-grade
fever, progressive truncal hypotonia, severe pyramidal and extrapyramidal signs, and
skin lesions. MRI may show diffuse white matter hyperintensity in T2/FLAIR with punctate
calcifications. Cystic change is known in this entity [Figure 4].
Figure 4 (A-F): Aicardi-Goutier syndrome - A 7-year-old boy presented with microcephaly, early onset
feeding difficulties, and developmental delay. Axial CT sections of the brain show
coarse calcifications in the dentate and cerebellar white matter (A) (black arrows), basal ganglia (black arrows), and subcortical white matter (black arrowheads) (B). (C and D) Axial T2WI reveals gross cerebellar and cerebral atrophy. There is
extensive frontal predominant white matter hyperintensity (white arrows). (E and F) Axial SWI shows punctate calcifications of the dentate and subcortical
white matter. CSF showed lymphocytosis and increased IFN-α Serology was negative for
TORCH infections
Metabolic, toxin, and drug-induced
Maple syrup urine disease shows enzymatic defect in the initial steps of the common
metabolic pathway for breakdown of branched-chain amino acids – leucine, isoleucine,
and valine – leading to the accumulation of corresponding keto acids. Infants generally
present with failure to thrive. CT shows a very characteristic pattern with profound
hypodensity and swelling of the cerebellar hemispheres including dentate, dorsal part
of the pons, midbrain, posterior limb of the internal capsule, the globus pallidus,
and often the thalamus. These areas appear hyperintense in T2 and show diffusion restriction.
MRS shows elevated branched chain amino acids and ketoacids at 0.9 ppm [Figure 5].
Figure 5 (A-D): Maple syrup urine disease - A 4-day-old infant presented with lethargy, poor feeding
convulsions, bulging fontanelle, and irregular respiration. (A) Axial T2WI shows hyperintensity
in the cerebellar white matter, dentate nuclei, pyramidal tracts (white arrows), and dorsal pons. DWI (B) and ADC (C) map shows diffusion restriction in the described
areas. (D) MRS at TE 135 ms shows prominent amino acid peaks at 0.9 ppm (white arrow)
Cerebro-tendinous xanthomatosis is a rare autosomal recessive disorder of lipid metabolism,
characterized by tendon xanthomas, early cataracts, mental deterioration, and spastic-ataxia.
Involvement of spinal cord is also noted in some cases. CT may show dentate calcifications.
MRI shows characteristic trilaminar appearance of the dentate, as shown in [Figure 6]. Hyperintense signal is also noted in supratentorial white matter, especially along
the posterior limbs of internal capsules.
Figure 6 (A-F): Cerebro-tendinous xanthomatosis - A 23-year-old wheel-chair bound male with multiple
subcutaneous swellings and mental retardation. (A) Clinical image of the right lower
limb shows subcutaneous swelling - tendon xanthomas. (B) Axial T2WI reveals trilaminar
appearance in the cerebellar hemisphere; hyperintensity in the core of the dentate
nuclei; surrounding hypointensity suggestive of calcification and cerebellar white
matter hyperintensity (white arrows). (C) and (D) images show subtle signal changes along the Corticospinal tracts (white arrows) and centrum semiovale. (E) SWI shows intense blooming of the dentate and adjacent
white matter (white arrows) (F) MRS at TE 135 ms shows inverted lactate peak from the cerebellar white matter
(white arrow) and decreased NAA peak (white arrowhead)
L-2 hydroxyglutaric aciduria has an autosomal recessive mode of inheritance. The age
of presentation is relatively older than that of Canavan’s disease. It is characterized
by elevated levels of l-2-hydroxyglutarate in urine, CSF, and plasma. Imaging shows
T2/FLAIR hyperintensity of the subcortical white matter, sparing the deep white matter.
Globus pallidus, caudate, and putamen are typically involved. Dentate may be involved.
Diffuse gliomas have also been reported with the condition [Figure 7].[6]
Figure 7 (A-D): L 2-hydroxyglutaric aciduria - Patient 1: A 4-year-old girl presented with ataxia,
nystagmus, dysarthria, slow intellectual decline, and dystonia. (A) Axial T2WI shows
hyperintensity in bilateral dentate nuclei and adjacent cerebellar white matter (white arrow). (B) Confluent signal changes in the supratentorial white matter with predominant
subcortical involvement (white arrowhead). Bilateral symmetrical signal changes are also noted in the striatum (white arrow). Patient 2: A 9-year-old boy presented with a long-standing history of seizures, extrapyramidal
symptoms, and ataxia. (C) Axial T2WI image shows signal changes similar to those of
patient 1. (D) A cystic lesion in the right anterior temporal lobe is noted (white arrow). Postcontrast scan (not shown) did not reveal any enhancement. Postoperative histopathological
examination showed a low-grade glioma
Glutaric aciduria type 1 is an autosomal recessive metabolic disorder caused due to
the deficiency of glutaryl CoA dehydrogenase enzyme. Most cases present during infancy
with acute encephalopathic illness along with seizures, hypotonia, and choreoathetosis
precipitated by fever, immunization, or surgical procedure. MRI shows a large head
size with wide open sylvian fissure due to failure of operculization, signal changes
in the basal ganglia, and bilateral subdural collections. Dentate may be occasionally
involved [Figure 8].
Figure 8 (A-D): Glutaric aciduria type-1 a 11/2-year-old boy presented with developmental regression after an episode of febrile
seizures at 9 months of age. Axial T2WI reveals hyperintense signal changes in the
central tegmental tracts (A) (white arrowheads), brainstem (B) (white arrows), and globus pallidus (C) (white arrows), with wide open sylvian fissures. (D) Coronal T2WI shows hyperintensity in lobar white
matter and dentate nuclei (white arrowheads)
Mucopolysaccharidoses represent a group of inherited lysosomal storage disorders characterized
by defective degradation of glycosaminoglycans. The clinical manifestations include
short stature, skeletal deformities, hepatosplenomegaly, hernias, coarse facial features
with cardiovascular, respiratory, and neurological abnormalities. MRI may show large
head size, with J-shaped sella, prominent perivascular spaces, and crowding at Foramen
magnum. Dentate may be involved [Figure 9].
Figure 9 (A-C): Mucopolysaccharidosis - A 21/2-year-old boy presented with facial dysmorphism, macrocephaly,
and developmental delay. (A) T2W sagittal image shows craniofacial disproportion,
J-shaped sella (white arrowhead) with crowding at the foramen magnum (white arrow). (B) and (C) T2W axial image shows T2 hyperintensity in dentate nuclei (white arrows). Posterior predominant prominent perivascular spaces in cerebral white matter are
noted (C) (white arrow)
Metronidazole toxicity is a known cause of abnormal T2 hyperintense signal change
in dentate nuclei. This toxicity generally presents with dysarthria, ataxia, and visual
blurring. Cumulative dose of 25–90 g administered over a period of 1–3 months is implicated.[3] Symptomatic as well as imaging reversal is noted post drug withdrawal [Figure 10].
Figure 10 (A and B): Metronidazole toxicity - A 31-year-old man presented with acute onset ataxia and
dysarthria. History revealed intake of metronidazole for 2 months. (A) Axial FLAIR
images reveal bilateral symmetrical hyperintensity in the dentate nuclei (white arrowhead), central tegmental tracts (white arrows), dorsal pons, and (B) posterior putamina (white arrows) and globi pallidi (white arrowheads). There was no evidence of diffusion restriction or postcontrast enhancement (not shown)
Isoniazid-associated cerebellitis has been described in patients on antitubercular
treatment with coexistent chronic renal disease. It can present with bilateral dentate
T2/FLAIR hyperintensity and diffusion restriction. Follow-up after withdrawal generally
shows resolution of signal changes.[7]
Fahr’s syndrome is an autosomal dominant disorder, presents in 4th to 5th decade characterized by progressive neurologic dysfunction and neuropsychiatric manifestations.
Biochemical abnormalities and somatic features suggestive of a metabolic disease or
infectious, toxic, and traumatic causes should be excluded. Extensive calcifications
can be seen in the subcortical white matter, basal ganglia, and dentate, as shown
in [Figure 11].
Figure 11 (A-H): Fahr disease - A 48-year-old male presented with tremors and slowness progressive
in nature. Noncontrast CT brain shows extensive coarse calcifications of the dentate
nuclei (A) (black arrow), thalami (black arrow), basal ganglia, and subcortical white matter (black arrowheads) (B). (C and D) Axial T1WI show patchy hyperintensity in these regions, T2WI shows
hypointensity (E and F). (G and H) SWI shows blooming in these regions suggestive
of calcification. Serum evaluation for other metabolic or systemic disorders was normal
Chronic lead poisoning is seen most commonly due to occupational exposure in workers
involved in the manufacture of lead pipes and batteries. They can present with nonspecific
neurologic manifestations such as dementia, diminished visual acuity, peripheral neuropathy,
syncope, dizziness, nystagmus, easy fatigue, and back pain. It can be associated with
extensive intracranial calcifications [Figure 12].[8]
Figure 12 (A-F): Lead toxicity - A 40-year-old worker in pipe manufacturing industry for the past
20 years presented with extrapyramidal features. Axial CT images show calcification
of dentate nuclei (A) (black arrow); basal ganglia (black arrow), thalami (curved arrow), and subcortical white matter (black arrowhead) (B). (C and D) T2W Axial MRI shows hypointensity in the dentate nuclei, thalami and
basal ganglia, hyperintensity is noted in the cerebellar white matter. (E and F) SWI
shows blooming in these regions. Serum evaluation for other metabolic or systemic
disorders was normal
Leigh disease or subacute necrotizing encephalomyelopathy is a progressive neurodegenerative
disorder caused by mitochondrial respiratory enzyme chain defects, characterized by
developmental regression, and is often associated with febrile episodes and is caused
by enzyme deficiencies of the respiratory chain complexes [Figure 13]. T2 hyperintensity is noted in the basal ganglia, brainstem, and dentate nuclei
with diffusion restriction and postcontrast enhancement, which may be seen in acute
stages. Involvement of brainstem and subthalamic nuclei has been described as an indicator
of SURF-1 mutations in cases of cytochrome oxidase deficiency.[9]
Figure 13 (A-D): Leigh disease with SURF-1 mutation - A 1-year- old girl presented with regression of milestones along with
feeding difficulties, following a febrile episode 4 months ago. (A) Axial T2WI reveals
bilateral symmetrical hyperintense signal in the caudate, putamen (black arrows). (B and C) Coronal T2WI shows bilateral symmetrical hyperintense signal in substantia
nigra (black arrows), subthalamic nuclei, and dentate nuclei (black arrowheads). Patchy areas of diffusion restriction and postcontrast enhancement were noted in
these regions (not shown). (D) MRS at TE 135 ms shows inverted lactate peaks at 1.33
ppm (white arrows)
Wilson’s disease is an autosomal recessive disorder with defect in copper metabolism;
it is characterized by abnormal accumulation of copper in various tissues, particularly
in the liver and brain. Flapping tremors are classical findings in neurological examination
along with Kaiser–Fleischer ring. MRI shows signal changes in basal ganglia, brainstem,
and dentate, with occasional hyperintensity of cortex and subcortical white matter,
especially frontal lobes [Figure 14].
Figure 14 (A-C): Wilson's disease - A 14-year-old girl with KF ring and hepatomegaly. Axial FLAIR
images of show bilateral symmetrical hyperintensity in the dentate nuclei and adjacent
cerebellar white matter (A) (white arrows), dorsal midbrain (B) (white arrow), thalami (white arrows), and basal ganglia (C) (white arrowheads)
Neurodegenerative
Neurodegeneration with brain iron accumulation (NBIA) is a group of progressive neurological
disorders that present with prominent extrapyramidal symptoms, intellectual impairment,
and iron deposition in basal ganglia. Ten forms of NBIA have been described to date,[10] of which neuroferritinopathy and aceruloplasminemia have been associated with iron
deposition in dentate nuclei [Figure 15] and [Figure 16].[11]
Figure 15 (A-D): Neuroferritinopathy - A 19-year-old female presented with extrapyramidal symptoms
progressive for the last 2 years. Axial FLAIR images show hypointense signal in the
dentate nuclei (A) (white arrowheads) and globus pallidus (B) (white arrows). These regions demonstrate blooming on GRE images (C) and (D)
Figure 16 (A-D): Aceruloplasminemia - A 27-year-old male with tremors and intellectual impairment
since 5 years. Axial T2WI images show bilateral symmetrical hypointensity in dentate
nuclei (A) (white arrows), thalami (white arrowheads), and putamina (white arrows) (B). Intense blooming is noted in GRE images in these areas (C and D). No signal
changes were noted in white matter
Inflammatory and infectious
Progressive multifocal leukoencephalopathy is a fulminating opportunistic infection
of the brain caused by John Cunningham virus (JC virus) in a setting of immunocompromised
status leading to myelin breakdown and oligodendrocyte destruction.[5] Diffuse but bilateral asymmetrical signal changes are noted in the supra- and infratentorial
white matter with involvement of subcortical areas [Figure 17]. Occasional postcontrast enhancement may be seen.
Figure 17 (A and B): Progressive multifocal leukoencephalopathy - A 40-year-old immunocompromised male
presented with altered sensorium. Axial FLAIR images show bilateral asymmetrical hyperintense
signal changes in the dentate nuclei (white arrowheads), middle cerebellar peduncles
(A) (white arrows) and (B) supratentorial white matter with subcortical involvement in the left frontal
lobe. Right-sided subdural hemorrhage was noted incidentally (white arrow)
Langerhans’s cell histiocytosis (LCH) presents with reactive clonal proliferation
of Langerhans cells, which are bone marrow-derived cells of dendritic cell line with
antigen presenting and processing properties. CNS imaging reveals craniofacial bones,
skull base and paranasal sinus invasion, involvement of meninges and hypothalamo-pituitary
axis is noted.[12] Patchy lesions with postcontrast enhancement may be seen; involvement of dentate
is common [Figure 18].
Figure 18 (A-D): Langerhans cell histiocytosis - A 30-year-old man presented with ataxia for 4 months
and hepatospenomegaly. (A) Axial T2WI shows bilateral symmetrical patchy hyperintense
signal change in the dentate nuclei (white arrows), which shows intense postcontrast enhancement (B). (C and D) Multiple other enhancing
punctate foci are noted in the subcortical white matter (white arrows). Histopathology from biopsy from temporal lobe showed findings consistent with LCH
Erdheim–Chester disease is a non-Langerhans cell form of histiocytosis characterized
by xanthomatous infiltration of tissues by foamy histiocytes. Multiple organ infiltration
is also noted in this entity, as in LCH. Diametaphyseal osteosclerotic lesion of long
bones showing increased uptake in Tc 99m bone scintigraphy form radiological diagnostic
criteria. Dentate involvement has been described in this entity.[13]
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease
affecting young adults mostly leading to severe and irreversible clinical disability.
The demyelinating plaques can be noted in the supratentorial (periventricular and
juxtacortical) as well as infratentorial parenchyma and spinal cord. Dentate involvement
has been described as T1 hyperintensity in unenhanced images, which are more commonly
associated with the secondarily progressive subtype.[14] T2 hypointensity in dentate has also been correlated with ambulatory impairment
in MS.[15]
[Figure 19].
Figure 19 (A-C): Multiple sclerosis - A 16-year-old girl presented with relapsing remitting neurological
illness since the last 2 years. (A) T2W sagittal image of the spine shows patchy short
segment hyperintensities in the cervicodorsal cord (white arrows). Similar signal changes are noted in bilateral dentate nuclei (white arrowheads), left middle cerebellar peduncle (B) (white arrow), medulla, and corpus callosum (C) (black arrow)
Miscellaneous
Gadolinium-based contrast agent (GBCA) exposure – Of the other causes of dentate involvement,
gadolinium deposition in dentate nuclei is important. It can be observed in patients
who require repeated imaging with GBCAs. The patients generally have preserved renal
function. Deposition is also seen in the globus pallidus and is most commonly associated
with use of gadodiamide (nonionic linear chelate). It is now considered that the T1
hyperintensity in the dentate nuclei of MS patients may be attributed to the repeated
exposure to GBCAs and gadolinium deposition given the repeated MRI done in these patients.[16] Recent studies performed on autopsy specimens proved that T1 shortening results
from gadolinium retention in neuronal tissues of the global pallidus, thalamus, dentate
nucleus, and pons [Figure 20].
Figure 20 (A-D): Gadolinium-based contrast agent deposition - A 15-year-old girl had relapsing remitting
neurological illness and had undergone 11 MRIs in the last 4 years. (A and B) Axial
T1WI shows hyperintensity in the dentate nuclei in the recent MRI (blackarrow); no obvious signal change was noted in globus pallidus. Axial T2WI reveals signal
change in the right posterior limb of internal capsule (C) white arrow) and periventricular white matter (white arrow)(D)
