Further Brain Magnetic Resonance Imaging (MRI) Delineation of Aicardi-Goutières Syndrome (AGS)
Amal Y. Kentab*
Department of Pediatric, Neurology Division, King Khalid University Hospital, King Saud University Riyadh, Saudi Arabia
Submission: January 19, 2019; Published: February 27, 2019
*Corresponding author: Amal Y. Kentab, Department of Pediatrics, Neurology division, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia
How to cite this article: Kentab AY. Further Brain Magnetic Resonance Imaging (MRI) Delineation of Aicardi-Goutières Syndrome (AGS) . Open
Access J Neurol Neurosurg. 2019; 9(5): 555771. DOI: 10.19080/OAJNN.2019.09.555772.
Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous disorder reported previously as an inherited congenital infection-like syndrome. It is characterized by an early onset progressive encephalopathy, brain calcification, leukodystophy, CSF chronic lymphocytosis, elevated CSF alpha-interferon, and negative results for common prenatal infections. It is autosomal-recessive or rarely autosomal-dominant and caused by mutations in one of several genes TREX1, RNASEH2A, RNASEH2B, and RNASEH2C, SAMHD1, IFIH1, and ADAR. The Magnetic resonance imaging findings of two male siblings diagnosed genetically with AGS 5 due to a homozygous mutation in SAMHD1 with very similar characteristics comprising profound psychomotor retardation, progressive microcephaly, spasticity, dystonic posturing, and tonic seizures are reported. The author reviewed the literature to delineate a specific MRI pattern of AGS.
Aicardi-Goutières (AGS) Syndrome is a rare genetically heterogeneous disorder. It was first described as a distinct Chronic Infection-Like Syndrome (CILS) with chronic CSF leukocytosis, basal ganglia calcification and a negative test for infection by Aicardi and Goutierés , Lanzi, et al. , and La Piana, et al. . It was further distinguished from other CILS by the classical bilateral calcification of the basal ganglia, leukoencephalopathy and/or cerebral atrophy.
It has a prevalence of 1-5/10,000. Currently, seven different types of AGS are described as mutations in 7 genes have been identified TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1 . AGS is generally inherited as an autosomal recessive trait although the dominant heterozygous gain of function mutations in TREX1, ADAR1, and all IFIH1 genes were observed . Mutations in these genes enhance the production of type 1interferon and upregulation of interferon-stimulated genes. Consequently, disturbance of both cellular and immunological function occurs, which results in elevation of interferon-α both in the CSF and blood .
Typically affected patients show severe, subacute encephalopathy characterized by irritability, feeding problems, psychomotor regression or delay associated with epilepsy (53%
of cases), chilblain skin lesions on the extremities (43% of cases) and episodes of aseptic febrile illness (40% of cases), progressive microcephaly, spasticity, and dystonia, often followed by death in early childhood [2,6,5]. It is phenotypically heterogeneous as it shows inter- and intrafamilial variations with a range of onsets between the first month of life usually with life-threatening illness and a less severe form described during late infancy with preservation of language skills and cognitive function, and a normal head circumference. The disease is rapidly fatal or progresses to a vegetative state .
Elevated IFN-alpha levels and CSF lymphocytosis are very frequent but not constant findings (90% and 75% of cases, respectively) at the initial stage of the disease but tend to normalize or resolve within a few years . Typical MRI features include early temporal lobe swelling followed by atrophy, early global cerebral atrophy and visible calcification .
Magnetic Resonance Imaging (MRI) findings of two male siblings diagnosed genetically with AGS 5 with very similar characteristics comprising profound psychomotor retardation, progressive microcephaly, spasticity, dystonic posturing, and tonic seizures are reported. The author reviewed the literature to delineate a specific MRI pattern of AGS.
This boy, currently 5 years old, was initially evaluated
because of global developmental delay and seizures at the age
of 5 months. He was the first child of healthy consanguineous
Saudi parents. There was no family history of epilepsy or
neurological disorders or neonatal deaths. He was a product of
term pregnancy and delivered by emergency caesarean section
due to meconium liquor. Head circumference at birth was 35.5
cm (at 50th percentile). He had mild, transient jaundice at birth.
Since the early neonatal period, he was noticed to have extreme
irritability and poor feeding. He had poor visual tracking and
hearing with no social smile. At 4 months of age, he had poor head
control, was not rolling and showed intermittent stiffness of his
limbs. He developed tonic seizures and episodes of spontaneous
clonic movements and staring at the age of 4 months. Epilepsy
was resistant to multiple antiepileptic medications, but he was
maintained on phenobarbitone, carbamazepine, topiramate,
and clonazepam with reasonable control. He had profound
developmental delay and inability to communicate or ambulate.
Examination at the age of 5 months showed a head circumference
of 32 cm (25th percentile), no response to visual stimuli, head
lag, axial hypotonia, and extremity hypertonia with hyperreflexia
in both arms and legs. Follow-up exam at one year of age showed
progressive spastic quadriplegia, and he developed joint
contractures despite oral baclofen and physiotherapy. Initial
evaluation included a normal abdominal ultrasound and dilated
ophthalmological examination. Brain MRI (at 4 months of age)
showed multiple subcortical cysts, extensive bitemporal cystic
lesions, and significant thinning of the brain stem and cerebellar
Brain CT scan during infancy showed calcification at
basal ganglia, and periventricular white matter (Figure 1, 2).
Metabolic testing was normal and included the following:
serum amino acids, plasma very long-chain fatty acids, plasma acylcarnitine profile, serum biotinidase level, serum ammonia,
lactate, and urine organic acids. Chromosomal microarray was
normal. Electroencephalogram (EEG) revealed slow background
and multifocal epileptiform discharges. Visual Evoked Potential
(VEP) and Brain Auditory Evoked Potentials (BAEP) were
normal. Cerebrospinal Fluid (CSF) testing at 4 months of age
showed normal cell count, protein, glucose, lactate and amino
acid content. A follow-up brain MRI at 4 years of age showed
severely atrophic brain parenchyma with enlargement of
ventricles, reduced bulk of cerebral white matter, thinning of
corpus callosum and brainstem. Cystic changes were noted
at bilateral frontal lobes, left parietal lobe, and tiny cysts in
anterior temporal lobes (Figure 3). Brain Magnetic Resonance
Angiography (MRA) obtained concurrently was normal. Further
molecular analysis confirmed Aicardi-Goutieres syndrome 5 due
to a homozygous mutation in SAMHD1 gene.
Patient 2 was the younger brother of patient 1. He was born
at term by normal vaginal delivery following an uneventful
pregnancy. Birth weight and head circumference were 3 kg
(10th percentile) and 32 kg (at 5th percentile), respectively. He
presented with a similar picture like his brother, though the
severity of symptoms was less. He had episodes of sterile pyrexia.
At the age of 5 months, he experienced partial tonic seizures
and EEG showed slow background activity with infrequent
sharp- and slow- wave activity at the tempro-occipital region.
Seizures were controlled by carbamazepine and topiramate.
Cranial CT performed at 8 months showed brain atrophy with
periventricular and basal ganglia calcification. On physical exam
at 1 1/2 years, he was noted to have a head circumference of 44
cm (< 5th percentile) with weight and length < 10th percentile.
He had spastic quadriplegia with intermittent dystonia with no
acquisition of motor skills.
EEG records showed background slowing associated with infrequent
sharp waves in the tempro-occipital region. Abdominal
ultrasound and ophthalmological examination showed normal
results. Brain MRI showed atrophic changes in the cortex, cerebellum
and brainstem, mild ventromegaly and white matter loss.
Aicardi-Goutières syndrome is a rare type of inherited leukoencephalopathy
with variable clinical manifestations. It has autoimmune
manifestations and large vessel vasculitis. Molecular
detection of specific gene mutations is required to confirm the
diagnosis, but certain neuroradiologic patterns can be detected
initially, which may facilitate more precise and earlier diagnosis
of this rare but probably underdiagnosed syndrome .
Both siblings in this report had the classic clinical picture of
neonatal onset AGS, with subacute encephalopathy manifested
with irritability, feeding problems, psychomotor delay, and
epilepsy. Episodes of sterile pyrexia were seen in the younger
sib. No autoimmune manifestations were recorded (chilblain
skin lesions, hepatitis, arthropathy, or cardiomyopathy). The
older sibling had primary hypothyroidism. They end with the
typical phenotype of progressive microcephaly, irritability,
spastic quadriplegia, dystonia, and GT insertion for feeding.
The younger sib had less severe symptoms with a much slower
course consistent with the previously reported data of inter- and
intrafamilial variation [4,9].
A homozygous mutation in SAMHD1 gene at 20q11.23 confirmed
the diagnosis of AGS 5. Currently prenatal diagnosis is
feasible through molecular analysis of amniotic fluid or trophoblasts.
Treatment is symptomatic, mainly for feeding problems,
spasticity, dystonia, epilepsy, and irritability with sleep disturbance.
AGS is classified under neurological disorders with mainly
leukodystrophy pattern on brain MRI . Earlier studies have
shown that the cardinal features for diagnosis are intracranial
calcification (involving the basal ganglia and white matter), cystic
leukodystrophy (predominantly frontotemporal) and early
cortical-subcortical atrophy. It is often associated with atrophy
of the corpus callosum, brain stem and cerebellum [9,10].
Brain calcifications were typically small, multifocal, and seen
mainly in the basal ganglia (putamina), lobar white matter, and
dentate nuclei, but the globi pallidi, thalami, deep and subcortical
white matter may be involved as well [8,11]. It identifies
correctly up to 94.44% of AGS with a sensitivity of 90.9% and a
specificity of 96.9%.
The subcortical and deep white matter typically are abnormal
and appear as hypodense lesions on CT, hypo intense on
T1-weighted image and high signal intensity on T2-weighted
image or FLAR image. These abnormalities are either diffuse or
with anteriorposterior gradient mainly lobar with early involvement
of subcortical arcuate fibers and with relative sparing of
the corpus callosum, the capsules, and the optic radiations .
Imaging studies may also show ventriculomegaly, usually progressive,
secondary to progressively reduced volume of white
matter in the cerebral hemispheres . In later stages of the
disease, white matter may have signal intensity similar to CSF,
particularly in the frontal lobes .
Both the calcification and white matter abnormalities
increased in the first 2 years after diagnosis before becoming
stable. Usually a significant degree of cerebral atrophy exists
which remains substantially stable with time or worsens in
The cerebellum and brainstem may be small [13,14], but
the cerebellar white matter is often spared. Abdel-Salm, et al.
 reported a rare finding of unilateral cerebellar hypoplasia
in a patient with homozygous missense mutation in RNASEH2B
The presence of deep white matter cysts in the temporal or
frontal lobes has been reported only in a few patients in certain
case series reports [3,12,16]. They represent a severe cystic
degeneration of the white matter and were commonly observed
in patients with TREX1 mutations . Early on, patients may
present with temporal lobe swelling followed by atrophy with
temporal horn dilatation . Furthermore, Olivieri, et al. 
and Abdel-Salam GM, et al.  reported the presence of small
and large porencephalic cysts, respectively.
A recent study by Al Mutiri F, et al.  described the neuroimaging
findings in a series of 24 patients; leukoencephalopathy
in 83 %, cerebral atrophy in 75 %, and calcification in 54 %.
Thinning of corpus callosum as well as ventromegaly in the absence
of hydrocephalus was also seen but to a lesser extent. Only
one patient was reported with white matter cysts. Follow-up
MRI showed improvement in myelination and a decreased degree
of atrophy with increasing duration of AGS.
In AGS 5 with SAMHD1 mutation, it is expected to have some
large vessels vasculitis with some vascular developmental variants
[4, 5], but brain MRA was normal for both siblings. Follow-
up of our patients showed further cerebral and white matter
atrophy with the collapse of previously reported cysts. The typical
pattern of MRI found in AGS (Table 1) helps to differentiate it
from other causes of early infantile leukoencephalopathy (Table
An algorithm of such differential diagnosis with and without
temporal lobe swelling was reported by Vanderver A, et al.  to
differentiate it from AGS based on MRI analysis. With increased
availability and high specificity of the MRI, detection of calcification
on CT scan is no longer essential for the diagnosis of AGS.
In conclusion, AGS is an underdiagnosed hereditary leukodystrophy
syndrome with a typical clinical picture of early irritability,
psychomotor retardation, and microcephaly as well as
combined pyramidal and extrapyramidal manifestations. This
report highlights the importance of early recognition of the typical
MRI pattern of AGS that can help in clinical diagnosis before
confirmation by molecular genetic studies, especially in patients
with microcephaly and intracranial calcification.