DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY

REVIEW

Intracranial calcification in childhood: a review of aetiologies and recognizable phenotypes JOHN H LIVINGSTON 1

| STAVROS STIVAROS 2,3 | DAN WARREN 4 | YANICK J CROW 5

1 Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds; 2 Academic Department of Paediatric Neuroradiology Royal Manchester Children’s Hospital, Central Manchester Foundation NHS Trust, Manchester; 3 Imaging Science, School of Population Health, University of Manchester, Manchester; 4 Department of Neuroradiology, Leeds Teaching Hospitals NHS Trust, Leeds; 5 Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Science Centre, Central Manchester Foundation Trust University Hospitals, Manchester, UK. Correspondence to John H Livingston, Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, UK. E-mail: [email protected]

PUBLICATION DATA

Accepted for publication 31st October 2013. Published online 30th December 2013. ABBREVIATIONS

AGS BLC CMV ICC LCC SWI SWS

Aicardi–Gouti
eres syndrome Band-like calcification Cytomegalovirus Intracranial calcification Leukoencephalopathy with calcification and cysts Susceptibility weighted imaging Sturge–Weber syndrome

Intracranial calcification (ICC) is a common finding on neuroimaging in paediatric neurology practice. In approximately half of all cases the calcification occurs in damaged, neoplastic, or malformed brain. For the large number of other disorders in which ICC occurs, no common pathogenetic mechanism can be suggested. Congenital infection, particularly with cytomegalovirus, accounts for a significant proportion of all cases. However, some genetic diseases, in
res syndrome, Band-like calcification, and RNASET2-related disease, particular Aicardi–Goutie may mimic congenital infection; therefore, a full consideration of the radiological and clinical features is necessary before concluding that congenital infection is the cause. In some disorders calcification is a universal finding, in others it is a frequent occurrence, and in some it is only an occasional finding. Characteristic patterns of calcification are seen in a number of conditions, and a systematic approach to the identification and description of radiological findings, taken together in the context of the clinical scenario, allows a diagnosis to be made in many cases. Nonetheless, there remain a number of presumed genetic disorders associated with ICC for which the underlying molecular cause has not yet been identified.

Intracranial calcification (ICC) refers to calcification within the cranial cavity, and is generally taken to mean calcification within the parenchyma of the brain or its vasculature. The term physiological calcification is used to indicate calcification when seen as part of normal ageing. It is arguable whether physiological calcification occurs anywhere other than in the pineal gland or choroid plexus. Therefore, with the exception of calcification in these areas, which rarely manifests in the first two decades of life, ICC occurring before the age of 20 years can be regarded as pathological. Traditional pathology teaching distinguishes between metastatic and dystrophic calcification. Metastatic calcification occurs as a result of systemic disorders of calcium metabolism, such as hypo- and hyperparathyroidism. All other ICC is considered as dystrophic, meaning calcification occurring as a result of pathologies within the brain itself. There is probably no pathological insult that cannot, in some circumstances, result in ICC. Thus, there is a potentially endless list of causes. However, for poorly understood reasons, there are certain disorders in which ICC is prominent and/or characteristic, so that its recognition has value for diagnostic purposes. It is this group of diseases which form the subject of our review. 612 DOI: 10.1111/dmcn.12359

HOW COMMON IS ICC? In 1986, Kendall and Cavanagh1 reviewed 18 000 computerized tomography (CT) images taken at Great Ormond Street Hospital between 1977 and 1983, and identified ‘pathological’ ICC in 1.6%. In just under half (43%) of these the cause was neoplastic. Adult studies of basal ganglia calcification suggest a prevalence of 6.6 per 1000 population.2 In paediatric neurology practice, the identification of ICC represents a common diagnostic starting point for investigation of a neurological disorder. PATHOLOGY The pathological findings described in disorders associated with ICC do not allow for a unifying pathogenetic hypothesis to be proposed. There is a relative paucity of paediatric neuropathology data. In adult studies of bilateral striopallidodentate calcification, also known as Fahr disease, calcium has been identified as the major element present in mineralized areas. However iron, arsenic, molybdenum, aluminium, manganese, cobalt, silver, copper, magnesium, phosphorus, and mucopolysaccharides have also been identified.2,3 In Fahr disease, calcification is usually present in the walls of capillaries, arterioles, and small veins; however, free intraparenchymal deposits have also been described. In a number of apparently aetiologically © 2013 Mac Keith Press

diverse disorders, such as Aicardi–Gouti
eres syndrome (AGS),4 Coats plus disease,5 and congenital cytomegalovirus (CMV) infection,6 calcification occurs in small vessel walls, but intraparenchymal calcification may also be seen.

THE RADIOLOGICAL IDENTIFICATION OF ICC Calcification may be demonstrated by plain film skull radiography, ultrasound, CT imaging and magnetic resonance imaging (MRI; Fig. 1). The sensitivity and specificity for the identification of ICC differs according to imaging modality, intra-modality technique, and the age of the patient. In newborn children, ultrasound has been shown to have a very high agreement with CT in the imaging of ICC related to congenital infection.7 However, the technique is limited by patient age, as closure of the fontanelles at around 18 months postnatally means that no acoustic window is available for older age groups. In addition, although ultrasound is highly sensitive to ICC, it has lower specificity, as highly echogenic areas may also be caused by haemorrhage, infection, inflammation, and oedema. The problem of differentiation between ICC and haemorrhage is not limited to ultrasound, but is also relevant to CT imaging. CT has been the imaging mainstay for the demonstration of ICC for many years. Even with the advent of MRI in the early 1990s, CT remained superior for the identification and delineation of ICC.8 On CT, ICC appears as areas of high density, with a comparable Hounsfield unit value to bone. However, it is not possible to unequivocally distinguish between haemorrhage and ICC in a single CT image. Follow-up imaging that demonstrates a change in appearance of a high-density focus is supportive, but not definitive, of the appearance being the result of haemorrhage. Calcium is a diamagnetic substance and has a very low magnetic susceptibility compared with surrounding tissue. With the adoption of MRI, standard T1- and T2-weighted sequences were found to be much less sensitive at detecting ICC than CT. Furthermore, depending on the structural and chemical characteristics of the lesion in question, ICC may appear as either high or low signal on T1- and T2-weighted sequences, as well as being difficult to differentiate from areas of haemorrhage. The introduction of T2*-weighted or gradient echo sequences was found to increase the sensitivity of MR to ICC considerably – although not to the same degree as CT.9 ICC is seen as areas of low signal dropout often termed ‘blooming artefact’. It is important to emphasize that a low signal area on a gradient echo image merely indicates the presence of mineralization, which could be due to iron, haemorrhage, or calcium. For this reason, some authors continue, rightly in our opinion, to advocate CT as an important adjunct to gradient echo MRI.10 Susceptibility weighted imaging (SWI) is a 3D gradient echo MR technique with high spatial resolution. SWI makes use of phase post-processing to accentuate the

• •

What this paper adds This review considers the many aetiologies of ICC and describes those disorders in which characteristic neuroimaging features may indicate the diagnosis. A diagnostic approach for the consideration of a scan with possible intracranial calcification is proposed.

paramagnetic properties of blood products such as deoxyhaemoglobin, intracellular methaemoglobin, and haemosiderin, as well as other substances including ICC.11 The advantage of SWI is that, if properly implemented, it can detect ICC to a similar,12 if not higher,13 sensitivity level than CT. SWI is capable of differentiating ICC from haemorrhagic foci within brain abnormalities,14,15 which, as discussed above, is a problem for CT. In current clinical practice, outside the neonatal period, the first imaging modality usually performed as a neurological investigation in paediatric patients is MRI. Thus, it is important to recognize its limitations for demonstrating ICC. If the recognition of ICC is of potential importance, it is best to liaise with the radiology department regarding the availability of SWI or gradient echo sequences. If there is uncertainty, or if SWI is not available, CT can be of great diagnostic value.

PATTERN RECOGNITION We have previously demonstrated that a systematic approach to describing the radiological features associated with the presence of ICC can identify characteristic patterns associated with specific disease entities.16 In that study a specific diagnosis was made in only 50% of the 119 patients, emphasizing that there remains a significant number of patients with ICC in whom an aetiological diagnosis is not made. This approach to radiological pattern recognition will be used here, with particular emphasis on the appearance/ shape of the calcification, and its topography within the brain. We have defined a limited number of descriptive terms that enable most types/patterns of ICC to be described. Although arbitrary, and to some extent subjective, we believe that these terms are an aid to systematic study of radiological phenotypes. CT and MRI provide different, and often complementary, information, so that the emphasis in this article will be on their combined use for optimal diagnostic yield. THE DIAGNOSTIC APPROACH TO ICC Four primary questions should be posed when considering a scan with possible ICC. (1) Is calcification present? Consideration should be given as to whether the appearances are consistent with ICC, or whether an alternative explanation such as haemorrhage or iron/manganese deposition could account for them. Such differentiation is not always straightforward or indeed possible. Further imaging studies or follow-up imaging may be required. If ICC is present, then its nature and location should be described; (2) Is there a brain malformation or atrophy/ Review

613

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(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

Figure 1: The identification of intracranial calcification (ICC) using different imaging modalities. (a) Dense calcification is readily apparent on a plain film skull radiograph. (b) Ultrasound image of a child with congenital cytomegalovirus infection. ICC is readily seen as highly echogenic areas in the left periventricular region. (c) Gradient echo axial MR image of an infant with congenital toxoplasmosis showing multiple low-signal spots within the cortex and white matter. The spatial resolution is poor in gradient echo images. Different imaging modalities provide complementary information. (d) CT image at normal brain window settings (e) CT image at bony window settings, and (f) T2-weighted axial MRI of the same patient. The location of ICC may be difficult to determine on normal brain window settings (d), whereas on the bone window settings (e) the cortical location is apparent. This is confirmed on the T2-weighted MR (f) by the low-signal ribbon seen at the depths of the gyri. (g) CT, (h) T2-weighted axial MR, and (i) susceptibility-weighted axial MR images from the same patient, illustrating the differing appearances of ICC depending on the modality used.

hypoplasia of brain structures? If so, can this be characterized further? (3) Is the white matter abnormal? If so, can the leukoencephalopathy be characterized further and a diagnostic pattern suggested? (4) Are there other radiological features, such as the presence of contrast enhancement, cysts or vascular abnormalities, that add further diagnostic information in selected cases? As always, the radiological data must be considered in the context of the clinical history, examination findings and other ancillary investigations.

FOCAL ICC IN TUMOURS AND FOLLOWING ACQUIRED BRAIN INJURY Overall, focal calcification occurring in damaged or neoplastic brain tissue accounts for at least half of all cases of 614 Developmental Medicine & Child Neurology 2014, 56: 612–626

ICC (Fig. 2). Calcification in tumours is common, and may be present in both malignant and benign neoplasms. It might be supposed that the presence of calcification indicates chronicity. However, the occurrence of calcification in malignant tumours indicates either that ICC may appear rapidly or that the presenting tumour represents a slower growing neoplasm that has undergone malignant transformation. Calcification within the basal ganglia or other brain regions is not uncommon following radiotherapy for treatment of a brain tumour, and has also been described in patients treated for leukaemia with combined cranial radiation and methotrexate. Dystrophic calcification, particularly in the cerebral cortex, is seen following brain damage due to bacterial

(a)

(b)

(c)

(d)

(e)

(f)

Figure 2: Examples of intracranial calcification (ICC) in acquired disorders. (a) A complex bilateral arteriovenous malformation. (b) Basal ganglia and deep cortical calcification in a 3-year-old presenting with a vein of Galen malformation. (c) Focal ICC following herpes simplex encephalitis. (d) Focal ICC in a desmoplastic infantile ganglioglioma. (e) ICC within a medulloblastoma. (f) Bilateral basal ganglia calcification 8 years after whole-brain radiotherapy treatment for a medulloblastoma.

meningitis, encephalitis, hypoxic–ischaemic injury and, sometimes, following ischaemic stroke. Focal calcification is common in vascular abnormalities such as arteriovenous malformations and, less commonly, cavernomata. Multiple calcified lesions may be seen in intracranial infections such as tuberculosis and cysticercosis. The aetiology of ICC in these disorders does not usually cause any major diagnostic difficulty, so that these conditions will not be considered further.

DISORDERS WITH METASTATIC CALCIFICATION Parathyroid disorders Hyper-, hypo-, and pseudohypoparathyroidism can all be associated with ICC.17–20 In these disorders the pattern of calcification is rather similar: symmetrical basal ganglia and thalamic calcification, often accompanied by deep gyral calcification. Hypoparathyroidism (Fig. 3c) usually presents with symptoms associated with hypocalcaemia, whereas pseudohypoparathroidism more typically presents with short stature, dysmorphic features, and developmental delay. Hyperparthyroidism is rare in children, and is more often secondary than primary. ICC is described in adults with hyperparathyroidism. Whether this occurs in childhood is unknown. Carbonic anhydrase deficiency type 2 This is a rare autosomal recessive disorder characterized by renal tubular acidosis, osteopetrosis, and ICC.21,22 Bone

marrow failure, such as occurs in other forms of recessive osteopetrosis, is not seen in carbonic anhydrase deficiency type 2. The pattern of ICC in published studies are similar to that observed in hypoparathyroidism, predominantly involving the grey matter with symmetrical basal ganglia, thalamic, and often deep gyral calcification.

NEPHROGENIC DIABETES INSIPIDUS ICC may occur in both nephrogenic and central diabetes insipidus.23–25 The calcification seen typically involves the basal ganglia and deep cerebral cortex. In an autopsy case, calcification was demonstrated within and around small blood vessels.23 The mechanism responsible for the observed ICC is not known, but it has been suggested that it may be as a result of repeated episodes of hyperosmolar dehydration. There does seem to be a correlation between the severity of the ICC and the duration of diabetes insipidus before diagnosis. However, given the similarity of this pattern of ICC to that observed in many other disease states, it seems unlikely that this is the only mechanism. CONGENITAL INFECTION Congenital infection is often viewed as the paradigm of disease states associated with ICC, and is usually the first diagnostic consideration suggested by clinicians and radiologists when ICC is identified. In published series, ICC is reported to occur in 30% to 90% of cases of congenital CMV infection,26–28 and in 50% to 80% of cases Review

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Figure 3: Examples of intracranial calcification (ICC) patterns in specific diseases. (a) Congenital cytomegalovirus infection showing true periventricular and cortical calcification, and extensive cortical malformation. (b) Congenital toxoplasmosis demonstrating dense periventricular aggregates and hydrocephalus. (c) Hypoparathyroidism secondary to chronic iron toxicity in thalassaemia. Symmetrical calcification in globus pallidus, caudate, thalamus, and left frontal cortex. (d) Fahr disease: extensive symmetrical and predominantly grey matter calcification. (e) Classical Aicardi–Goutie
res syndrome: calcification in basal ganglia and deep white matter with marked low density and swelling of frontal white matter. (f) Band-like calcification with simplified gyration and polymicrogyria secondary to OCLN mutations showing a malformed brain with frontoparietal polymicrogyria and linear or reticular calcification in the deep cortex. (g) Leukoencephalopathy with calcifications and cysts. Note that the calcification is largely in the grey matter, and is similar to that seen in some cases of Fahr disease in (d). There are, however, large cysts arising in the thalami. There is also low density of white matter indicative of leukoencephalopathy. (h) COL4A1 mutation showing spot calcification in the deep frontal white matter on the left and true periventricular calcification on the right. There are also features of periventricular leukomalacia. (i) Juvenile Alexander disease showing calcification within periventricular garlands. (j) Cockayne syndrome with widespread calcification in deep white matter, deep cortex, and basal ganglia in an atrophic brain. Calcification was not suspected from the MR appearances. (k) Infantile Krabbe disease showing calcification with the corona radiata. (l) Molybdenum cofactor deficiency demonstrating bilateral thalamic calcification in an atrophic brain with some cystic encephalomalacia.

of congenital toxoplasmosis.7,29 Congenital CMV infection is relatively common, and therefore it is likely to account for a significant proportion of all cases of ICC. As MRI has become the first imaging modality of choice, ICC has been detected less frequently and the diagnosis of congenital infection depends on the identification 616 Developmental Medicine & Child Neurology 2014, 56: 612–626

of other clinical and radiological features. This is less of a problem in the neonatal period since cranial ultrasound will often suggest the presence of ICC and, thus, direct appropriate investigations. However, in older children with an undiagnosed neurological disorder, CT should always be considered if MRI is uninformative.

It is likely that congenital infection is the cause of some, and possibly many, examples of unexplained ICC. With the exception of CMV, the definitive diagnosis of congenital infection is difficult, or not possible, in the older child, which emphasizes the importance of identifying patterns of ICC that enable other diagnoses to be made or excluded.

Congenital CMV In the neonatal period, the diagnosis of congenital CMV may be straightforward in a child presenting with active infection with fevers, jaundice, hepatosplenomegaly, anaemia, thrombocytopenia and retinopathy (Fig. 3a). However, with the exception of retinopathy, this picture can also be caused by AGS30 and other rare genetic disorders (see below), so that definitive evidence of viral infection must always be sought. In the older child presenting with microcephaly, a motor disorder, cognitive delay and epilepsy with or without sensorineural deafness, the diagnosis of congenital CMV is more difficult. However, the MR features are often characteristic even where ICC is not identified.31 In spite of a relative paucity of published CT data, characteristic features of ICC in CMV can be defined. Calcification is often truly periventricular, in the ependymal or subependymal region, and seen as spots or lines or, on occasions, completely outlining the ventricles. Spots of calcification in the basal ganglia, white matter, or cortex may occur, and are often asymmetrical. The association of these features with patchy white matter abnormalities, cortical malformation, and anterior temporal ‘cystic’ abnormalities is highly suggestive of CMV. In the absence of positive identification of CMV on neonatal blood spot, care must be taken to rule out a possible genetic cause. For example, these radiological features (with the exception of cortical malformation) can be seen in patients with either AGS or RNASET2 mutations (see below). Congenital rubella This is exceptionally rare in developed countries, but is occasionally seen.32 The radiological features are similar to those of CMV infection. Multifocal white matter abnormalities are often present, and periventricular and basal ganglia calcification is seen. Congenital toxoplasmosis This continues to be an important cause of preventable and treatable morbidity, with widely varying prevalence throughout the world (Fig. 3b). Recently, it has become apparent that the presence of specific genetic polymorphisms may be associated with the development of brain and eye disease following in utero infection with Toxoplasma.33 A recent study of 33 cases of proven congenital toxoplasmosis identified ICC in 18 cases; interestingly, ultrasound

and CT were equally sensitive in detecting ICC.7 Compared with CMV infection, cortical malformations are not common in toxoplasmosis. By contrast, hydrocephalus is relatively frequent. True periventricular calcification with spots or rocks is seen, as is basal ganglia and cortical calcification. Improvement or disappearance of ICC with treatment has been well documented in congenital toxoplasmosis.

Other congenital infections ICC is well documented in association with many other infections including herpes simplex virus,34 varicella,35 parvovirus,36 in utero-acquired human immunodeficiency virus infections37 and lymphocytic choriomeningitis.38 However, the number of reported cases is too low to determine if characteristic patterns occur. CYSTIC LEUKOENCEPHALOPATHY WITHOUT MEGALENCEPHALY (RNASET2 MUTATIONS) Mutations in RNASET2 are associated with an autosomal recessive disorder characterized by early-onset severe developmental problems, often microcephaly, seizures, and sometimes hearing impairment.39,40 The imaging features are similar to those of congenital CMV infection, with multifocal white matter abnormalities and anterior temporal cystic abnormalities. Cortical malformation has not been described. Subtle spot calcification of the basal ganglia, periventricular, and deep white matter is seen in some but not all patients. This disorder is caused by mutations in the RNASET2 gene, which have been hypothesized to result in accumulation of ribosomal RNA within neuronal lysosomes. It is important to be aware of this condition, as it may be clinically and radiologically indistinguishable from congenital CMV infection. ‘PSEUDO TORCH’ This term has been coined by several authors to describe a heterogeneous group of patients sharing the clinical features of intracranial calcification, early-onset (usually severe), neurological abnormalities, and microcephaly with or without various other clinical features such as corneal clouding, cataracts, hepatosplenomegaly, and thrombocytopenia.41–48 Most reports describe more than one affected sibling, and therefore it is likely that these represent genetic diseases. The molecular basis of some of these conditions has now been identified (e.g. AGS and Band-like calcification [BLC] with simplified gyration and polymicrogyria). Nonetheless, the cause of many such examples of familial congenital infection-like disorders remains to be determined (Table I). In our opinion, the designation ‘pseudo TORCH’ does not add diagnostic specificity, and is probably best avoided. AICARDI–GOUTI
ERES SYNDROME The identification of the molecular basis of most cases of AGS (Fig. 3e) has provided major insights into disease pathogenesis and, in particular, why this disorder can Review

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618 Developmental Medicine & Child Neurology 2014, 56: 612–626

Yes

No

Yes Yes

No

Yes (2)

Yes (10)

Yes (2)

Yes (4)

Yes (2)

Yes (2)

No (2)

Yes (5) No

Yes (2)

Yes(3)

Yes (3)

Samson et al.88

Reardon et al.44

Yoshimara et al.103

Al-Dabbous et al.45 Al-Gazali et al.104

Slee et al.105

Adderson et al.106

Vivarelli et al.46 Kalyanasundaram et al.107 Knoblauch et al.47

Longman et al.108

McKinlay Gardner et al.109

NA

No

Yes (1) Post-natal

Yes

No

Yes

Yes

1/2

Yes (2)

Bonneman et al.102

Yes Yes

Yes

Yes (2) Yes (2)

Yes (2)

Microcephaly

Ishitsu et al.42 Burn et al.43

Baraitser et al.

41

Familial (number)

NA

No

No

No NA

NA

Cataract, microphthalmia, microcornea

NA

No

NA

No

NA

No Corneal clouding Retinal dystrophy (1)

No

Eye abnormality

No

No

Yes

Yes Yes

Yes

Yes

No

Yes

Yes

Yes

No

Yes

Yes No

Yes

Seizures

Periventricular and deep white matter, brain stem

Periventricular Plate-like superficial cortex, thalamus Plaque-like calcifications, cerebral hemispheres, brain stem, and cervical spine Globus pallidus/putamen

Globus pallidus, basal ganglia, cerebellar, white matter Basal ganglia, cortical

White matter, basal ganglia, brain stem, spinal cord, progressive Periventricular, cerebellar, thalamus Periventricular

Different patterns in different sibships

Frontal periventricular plaques

Thalamic, white matter, cerebellar White matter, extensive Ependymal, basal ganglia, cortical Basal ganglia, white matter, brain stem

Location of calcification

Table I: Summary of reported familial and non-familial patients with intracranial calcification of unknown aetiology

No No

No

1/2

Yes

No

2/5 No

No

No

No

Yes No

No

Yes

NA

Yes

No

No

No

3/5

No

No

No Yes

No

Hepatosplenomegaly

2/5

No

NA

No No

No

Cerebellum abnormal

No

No

1/2

2/5 No

Yes

No

No

No

Yes (1)

2/5

No

No

No Yes

No

Thrombocytopenia

Craniosynostosis and dysmorphic Neuropathology: multiple areas of ‘necrosis’

Intracranial haemorrhage, axillary calcification, cerebellar hypoplasia

Absent B cells, pancytopenia, hearing loss, hydrocephalus (1), white matter abnormal in one Cerebellar hypoplasia

Short limb dwarfism and intracranial haemorrhage

Extensive polymicrogyria Growth hormone deficiency. Abnormal white matter on magnetic resonance. Demyelination on autopsy Lactic acidosis, heterotopias and abnormal complex 1 and 4 One family resembles Aicardi–Goutie`res syndrome Renal tubular acidosis

Other

Review

619

No (1)

No

No

No

No

Mizuno et al.113

Kuki et al.114

Orcesi et al.115

Nakamura et al.116

Yes (3)

Kulkarni et al.48

Elsaid et al.

Yes (8)

Rajab et al.111

112

Yes (2)

Familial (number)

Hadchouel et al.110

Table I: Continued

Yes

Postnatal

No

No

Yes

No

Yes

Yes (Postnatal)

Microcephaly

No

No

No

No

No

No

No

No

Eye abnormality

No

No

Yes

No

No

Yes

No

No

Seizures

White matter, posterior limb of internal capsule, thalamus, dentate Striking deep cortical ribbon and basal ganglia

Periventricular, linear and basal ganglia Deep and periventricular white matter

Deep gyral, basal gangia, thalamus Corpus callosum, globus pallidus, deep white matter Cortical plate/band

Deep white matter, thalamus

Location of calcification

Hypoplasia

No

Eventual atrophy

Yes

No

No

No

Cysts

Cerebellum abnormal

No

No

No

No

No

No

No

No

Hepatosplenomegaly

No

No

No

Yes

No

No

No

No

Thrombocytopenia

Pontocerebellar and smooth cortex

Sensorineural deafness, marked leukoenecphalopathy Sensorineural deafness, progressive disease

Simplified gyration/ polymicrogyria, dysmorphic Pancytopenia, low thalamus cells

Intestinal pseudoobstruction and neuropathic bladder Growth delay, mod cognitive delay Dominant, mild clinical phenotype

Other

Table II: Other disorders in which intracranial calcification has been described Disorder

Source

Nasu–Hakola disease

van der Knaap and Valk117 Martinez-Saez et al.118

Hereditary diffuse leukoencephalopathy with spheroids Fried syndrome/AP1S2 Hereditary spastic paraparesis due to CYP2U1 mutations Degos disease Dihydropteridine reductase deficiency Cerebrotendinous xanthomatosis Oculo-dento-digito dysplasia Papillon–Lefevre syndrome Adams–Oliver syndrome Gorlin syndrome (calcification of the falx) Raine syndrome

Borck et al.119 Tesson et al.120 Yeo et al.121 Gudinchet et al.122 Barkhof et al.123 Barnard et al.124 Verma et al.125 Unay et al.126 Lo et al.127 al-Mane et al.128

mimic congenital infection. AGS is a type 1 interferonopathy that is caused by mutations in any one of the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR1.49–52 There are patients with AGS who do not have mutations in any of these genes, suggesting that there is at least one other gene associated with this phenotype. All of the identified genes are involved in the metabolism of nucleic acids, and possibly retroelements, sequences of nucleic acids derived from prior (ancestral) viral infection. In the presence of dysfunctional AGS protein, it is hypothesized that such retroelements initiate a type 1 interferon-mediated immune disturbance, resulting in a clinical state reminiscent of (exogenous) viral infection. The typical presentation of AGS is either as a neonatal encephalopathy resembling congenital infection or as infantile onset of an initially progressive disorder.53 The neonatal presentation is frequently characterized by fever, seizures, hepatosplenomegaly, thrombocytopenia, and anaemia, with or without microcephaly. The infantile form presents after a period of apparently normal development with the onset of severe encephalopathy, with irritability, fevers, loss of skills, and acquired microcephaly. After several months, the disease seems to stabilize and does not usually progress thereafter.54 Whilst these classical descriptions encompass the majority of cases identified to date, an increasing number of atypical presentations of AGS are now recognized. These include asymptomatic or very mildly affected patients, patients presenting later in childhood with neurological features, or patients with chilblains and no neurological features. Furthermore, affected siblings may differ markedly in the severity of disease, suggesting that additional genetic or environmental factors contribute to the phenotype.55 It has also become apparent that specific clinical features may be seen according to genotype. Most particularly, SAMHD1 mutations are frequently associated with cerebrovascular disease involving middle-sized and large 620 Developmental Medicine & Child Neurology 2014, 56: 612–626

vessels, resulting in moya-moya disease, intracerebral haemorrhage, and stroke.56 Furthermore, ADAR1 mutations may present with bilateral striatal necrosis and resultant severe dystonia. ADAR1 mutations may also cause the autosomal dominant disorder dyschromatosis symmetrica hereditaria. Rare patients with dyschromatosis symmetrica hereditaria have been described with a progressive dystonia associated with marked white matter and basal ganglia calcification.57,58 The imaging features of AGS have been well characterized, enabling a classical phenotype to be described that is virtually pathognomonic of the disease.16,59 As already emphasized above, optimal diagnostic information comes from considering both the MR and CT appearances. The MR features in the classical severe presentation are highly characteristic, and may suggest the diagnosis even if ICC has not been documented.16,56 To date, a cortical malformation has never been described in mutation-proven AGS, and it seems reasonable to assert that the presence of such a malformation excludes the diagnosis. The typical pattern of ICC is of symmetrical, spot-like lesions in the basal ganglia and the deep white matter of frontal and parietal lobes. True periventricular calcification, such as occurs in congenital infection, is relatively rare in AGS (and seems useful in the discrimination of these two entities). ICC can occur in other sites, such as the dentate, cerebellar cortex, brainstem, and occasionally deep or superficial cerebral cortex. In mild or asymptomatic cases of AGS, imaging can reveal only very mild abnormalities, for example, subtle spot calcification or even completely normal MR appearances.

OTHER TYPE 1 INTERFERONOPATHIES Spondoenchondrodysplasia Spondoenchondrodysplasia is a skeletal dysplasia associated with a wide range of autoimmune phenotypes including lupus. It has recently been shown that spondoenchondrodysplasia is caused by mutations in the ACP5 gene encoding tartrate-resistant acid phosphatase.60 All patients demonstrated upregulation of type I interferon signalling. CT imaging in four out of six patients revealed symmetrical ICC in the globus pallidus, putamen, and deep cortical grey matter. Systemic lupus erythematosus ICC is a well-recognized feature of systemic lupus erythematosus.61,62 Increased type 1 interferon expression is frequently demonstrated in individuals with systemic lupus erythematosus. COL4A1 MUTATION-RELATED DISEASE Mutations in the gene encoding the alpha 1 chain of type 4 collagen (COL4A1), a major component of vascular basement membranes, are a recently recognized cause of a genetic small-vessel disease affecting the brain, eyes, and kidneys. COL4A1 mutations (Fig. 3h) can lead to intracerebral haemorrhage and ischaemic damage that may have an

ante-, peri-, or postnatal onset.63–66 Characteristically, but not exclusively, the disorder is associated with the presence of porencephaly. Recently, COL4A1 mutations have also been demonstrated in patients with schizencephaly and also focal cortical dysplasia.67 Children with COL4A1-related disease often present with early-onset seizures, developmental delay, and cerebral palsy, with or without extraneurological features such as cataract and other eye abnormalities. As well as porencephaly, MRI often shows features of periventricular leukomalacia, namely high signal on T2weighted and fluid-attenuated inversion recovery (FLAIR) sequences in the periventricular white matter extending into the centrum semiovale. This is associated with loss of periventricular white matter volume, with cortical sulci almost reaching the margins of the ventricles in places and angular dilatation of the lateral ventricles. We have recently demonstrated that ICC may be present in patients with COL4A1 mutations, a feature which sometimes misleads clinicians as to the possible aetiology.68 The ICC was often subtle, and commonly present as periventricular, basal ganglia, or deep white matter spots. Pontine calcification was present in one patient. Recently, mutations in the COL4A2 gene have also been identified as a cause of familial porencephaly.69 It is likely that ICC can occur in this disorder. ICC occurs in areas of haemorrhagic or ischaemic damage, such as can occur in periventricular leukomalacia resulting from other aetiologies. However, the presence of basal ganglia or deep white matter calcification is not usual in prematurity-related periventricular leukomalacia.

COATS PLUS DISEASE AND LEUKOENCEPHALOPATHY WITH CALCIFICATION AND CYSTS Mutations in the gene encoding conserved telomere maintenance component 1 (CTC1) were recently reported as the cause of Coats plus disease (Fig. 3g). This is a multisystem disorder characterized by retinal telangiectasia and exudates (Coats disease), ICC with an associated leukoencephalopathy and brain cysts, osteopenia with a tendency to fractures and poor bone healing, and a high risk of lifelimiting gastrointestinal bleeding and portal hypertension caused by the development of vascular ectasias in the stomach, small intestine, and liver.70–72 The neuroimaging features of Coats plus disease are largely identical to those of the disorder described by Labrune et al.73 in 1996 as leukoencephalopathy with calcification and cysts (LCC). Before the identification of the CTC1 gene as the cause of Coats plus disease, it was postulated that LCC and Coats plus disease were different presentations of the same disorder given the designation cerebroretinal microangiopathy with calcifications and cysts or CRMCC.5,74 It is now recognized that Coats plus disease and LCC are distinct disorders, albeit sharing remarkably similar neuroimaging features. No patient with LCC has been identified to have a CTC1 mutation. Thus, the pri-

mary distinguishing feature between these diseases is that LCC is a purely neurological disorder, whereas patients with CTC1 mutations develop a multisystem disorder as described above. It is possible that the LCC phenotype represents more than one condition, which are likely to have a genetic basis as several sibling pairs have been identified. The radiological features of these disorders comprise a triad of leukoencephalopathy, ICC, and intraparenchymal cyst formation. The leukoencephalopathy is usually, but not always, symmetrical, sometimes has a posterior greater than anterior gradient, and is characterized by confluent high signal on T2-weighted and FLAIR sequences involving periventicular, deep and, sometimes, subcortical white matter. In unaffected areas myelination appears normal. Cysts are usually multiple, and often have a significant mass effect with surrounding oedema. The most common sites for cyst development are the centrum semiovale, basal ganglia or thalami, brain stem, and cerebellum. Early CT may show diffuse blush-like calcification before denser aggregations develop. Calcification is often readily apparent on MRI. On CT it is characterized by rock-like calcification of the basal ganglia, thalami, dentate, and deep cortex. Spot calcification within the deep white matter is common. Midbrain or pontine calcification may occur, and calcification within the walls of the cysts is common. The calcification pattern alone is not diagnostic. However, when combined with the leukoencephalopathy and cysts it is probably pathognomonic. A striking feature of both Coats plus disease and LCC is that cerebral atrophy does not occur, even when the disease is advanced. ICC has been demonstrated in other telomere-related diseases including dyskeratosis congenita,75 Revesz syndrome, and Hoyeraal–Hreidarsson syndrome.76,77

BAND-LIKE CALCIFICATION WITH SIMPLIFIED GYRATION AND POLYMICROGYRIA This rare autosomal recessive disorder has a striking radiological phenotype that readily allows differentiation from other conditions.78,79 It is an example of a disorder previously described as ‘pseudo TORCH’ that can now be diagnosed according to radiological and molecular characteristics. BLC (Fig. 3f) is caused by mutations in the OCLN gene, encoding the tight junction protein occludin.80 BLC is a severe disorder presenting at birth, or shortly after, with epileptic seizures, feeding difficulties, microcephaly, quadriplegia, and bulbar palsy. The radiological phenotype is best appreciated by considering both the CT and MRI appearances. There is a generalized malformation of the cerebrum with very primitive sulcation, giving an hour-glass appearance to the cerebral hemispheres. The gyration is abnormal, with a ribbon-like, sclerotic-looking cortex with areas of polymicrogyria. There is a frontoparietal predominance of the cortical malformation. The cerebellum, brain stem, and corpus callosum are hypoplastic in most patients. There is a marked reduction in white matter volume, with abnormal high T2-weighted signal and a lack of normal myelination. The ICC is usually readReview

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ily apparent on MR as a high T1-weighted, low T2weighted signal cortical band. On CT, calcification is seen as a symmetrical continuous or semicontinuous ribbon of cortical calcification with a reticular pattern in some. There is also symmetrical thalamic and central pontine calcification, although cerebellar calcification has not been seen to date. The brain malformation and calcification pattern seen in BLC are distinct from that seen in congenital CMV infection, which is the most common cause of ICC with polymicrogyria. It is not yet known whether milder phenotypes occur, and if they might show radiological overlap with congenital infection cases.

JAM3 MUTATIONS This is a recently described, most likely rare, recessive disorder characterized by severe intrauterine destructive damage due to intracranial haemorrhage, with associated subependymal calcification, microcephaly, congenital cataracts, and early death.81 The disease is caused by mutations in the gene encoding junctional adhesion molecule 3, a protein that, like occludin, is involved in the integrity and maintenance of tight junctions. GENETIC NEURODEGENERATIVE DISEASES ICC may occur in some neurodegenerative diseases. With the exception of Cockayne syndrome, in which it is a common and important diagnostic feature, in most instances ICC is only an occasional finding of little diagnostic help. Cockayne syndrome Cockayne syndrome (Fig. 3j) is an autosomal recessive disease caused by mutations in the nucleotide excision repair genes CSA and CSB. It is a multisystem disease with a spectrum of severity ranging from a severe antenatal-onset form, through to a milder later onset form with survival into adulthood.82 Characteristic clinical features are failure to thrive, developmental delay, cutaneous photosensitivity, sensorineural deafness, retinal dystrophy, dwarfism, and abnormal teeth. On MRI, hypomyelination is prominent as is white matter volume loss. Cerebral atrophy and early cerebellar atrophy are common. On CT, calcification is often, but not always, present early in the clinical course. Typically, there is symmetrical basal ganglia rock or spot calcification, with or without deep gyral calcification. Cerebellar, dentate, and thalamic calcification may occur, as may calcification of the leptomeningeal vessels. Overall, the associated ICC seems to progress with age. Krabbe disease ICC was described in older pathological reports and CT-era papers on infantile Krabbe disease (Fig. 3k).83 We recently reported three patients with otherwise typical infantile Krabbe disease demonstrating calcification in the internal capsule and corona radiata, presumably within areas of abnormal white matter and globoid cell 622 Developmental Medicine & Child Neurology 2014, 56: 612–626

accumulation.84 The radiological and clinical features were otherwise typical of the disease, serving to emphasize that the significance of ICC should be interpreted in the context of all the other radiological and clinical findings.

X-linked adrenoleukodystrophy In the pre-MR era, several reports described ICC in children with X-linked adrenoleukodystrophy.85 This usually presented within low density areas of abnormal white matter although in one case the calcification was periventricular. Alexander disease Focal calcification has been described within the abnormal white matter on histological examination of infantile and adult Alexander disease (Fig. 3i). A recent report of juvenile Alexander disease demonstrated ICC within the characteristic periventricular garlands.86 Mitochondrial disease The clinical and radiological features of mitochondrial disease are protean, and it is not surprising that ICC has been reported in this context. Indeed, it is perhaps surprising that ICC is not seen or described more often in association with mitochondrial dysfunction. The most welldocumented disorder in which ICC has been described is mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS), in which basal ganglia calcification has been described in 54% of patients. The youngest reported case was 17 years of age.87 Samsom et al.88 described two siblings with a severe fetal onset disorder associated with antenatal ICC, in whom complex 1 and 4 deficiency and pyruvate dehydrogenase deficiency were identified. In our recent series of ICC patients,16 we ascertained one infant with severe lactic acidosis, complex 2 and 3 deficiency and focal cortical calcification. Sulfite oxidase and molybdenum cofactor deficiency Sulfite oxidase and molybdenum cofactor deficiency (Fig. 3l) most typically present with a severe neonatal encephalopathy associated with severe destructive type changes on neuroimaging. The imaging features are often initially attributed to hypoxic–ischaemic encephalopathy. Highly echogenic areas suggestive of calcium or haemorrhage may be seen on ultrasound. CT may show highdensity areas and MRI can reveal high signal areas on T1-weighted and low signal on T2-weighted MRI, suggestive of calcification. ICC has been demonstrated in some pathological studies.89,90 Fabry disease A characteristic pattern of bilateral pulvinar calcification on CT and high signal on T1-weighted MRI is described in adults with Fabry disease.91 This seems to be a function of age, and has not to our knowledge been described

before the third decade of life. ICC may also involve the globus pallidus, deep gyri, and cerebellar folia.

FAHR DISEASE There is much confusion surrounding the use of Fahr disease (Fig. 3d) as a diagnostic term. A recent review noted that at least 35 different names had been used in publications to describe the ‘disease’, including the synonyms bilateral striopallidodentate calcification and idiopathic basal ganglia calcification.2 Published studies have employed differing inclusion criteria and often provide little detail of the radiological features. Even the more systematic studies often do not include a detailed consideration of the radiological phenotype. Although some authors suggest that the term bilateral striopallidodentate calcification should replace Fahr disease, this does not accurately reflect the calcification pattern in many of the reported cases – that often involves cortical grey matter, thalamus, and, sometimes, deep white matter. Fahr disease is not a single entity, and is likely to encompass different disorders resulting in a common and, thus, by definition, non-specific pattern of calcification. Familial and sporadic forms occur; some patients are asymptomatic, but in others a wide spectrum of clinical manifestations have been described, most commonly movement disorders, cognitive impairment, and psychiatric disease. The molecular basis of some familial forms of Fahr disease has recently been identified. Mutations in the SLC20A2 gene, encoding the type III sodium-dependent phosphate transporter, have been reported in Fahr disease pedigrees from China, Brazil, and Spain.92 Mutations in the PDGFRB gene have recently been observed in a large French pedigree.93 Interestingly, this gene is involved in the regulation of inorganic phosphate via a transporter encoded by SLC20A1, thus suggesting a possible common mechanism involving phosphate transport in these two disorders. Paediatric cases were reported in both of these studies, and we have recently identified a SLC20A2 mutation in a 12-year-old female and her mother. The calcification in Fahr disease is typically symmetrical, and predominantly involves grey matter structures – caudate, putamen, globus pallidus, thalamus, deep cortex, dentate, and sometimes cerebellar folia. White matter calcification is not prominent, but may occur. EPILEPSY, OCCIPITAL CALCIFICATIONS, AND COELIAC DISEASE This is a rare disorder that has mostly, but not exclusively, been reported in Italian, Argentinian, and Spanish patients.94,95 The epilepsy is often drug-resistant, and early diagnosis and dietary treatment can greatly improve epileptic seizure control. Characteristically, there is symmetrical and dense gyriform (deep and superficial) calcification in the parietooccipital cortex, and sometimes frontal or temporal cortex. There is often associated low attenuation of the underlying white matter on CT. In many of the reported cases, low

blood folate levels were identified – leading to the suggestion that this was an important factor contributing to the calcification. Recently, antibodies to transglutaminase isoenzyme 6 were identified in a patient with this syndrome, suggesting an autoimmune mechanism such as has been identified in other extraintestinal manifestations of glutenrelated disease.96

NEUROCUTANEOUS SYNDROMES ICC occurs in many neurocutaneous syndromes, in particular tuberous sclerosis, neurofibromatosis types 1 and 2, and Sturge–Weber syndrome (SWS).97 In tuberous sclerosis, calcification occurs both in the subependymal nodules and in the cortical tubers. With the exception of SWS, calcification in the neurocutaneous syndromes occurs in dysplastic, hamartomatous, or neoplastic tissue, and is usually focal or asymmetrical. In SWS a different mechanism may be involved, where the calcification is presumed to result from cortical or subcortical ischaemia secondary to the vascular disturbance associated with the pial angiomatosis. Typically, calcification is cortical and gyriform, and may involve the deep or superficial cortex or both. Calcification is often progressive, and may also involve the subcortical white matter. Recent multimodality imaging studies in SWS have demonstrated abnormal trans medullary veins in the white matter adjacent to abnormal cortical areas.98,99 In bilateral SWS with extensive ICC, the appearances can somewhat resemble BLC with simplified gyration and polymicrogyria. In SWS there is calcification in the walls of the angiomatous vessels, but also free parenchymal deposits within the superficial and sometimes deep cortex underlying the vascular malformation. Recently, somatic mosaicism of mutations in the GNAQ gene have been identified as the cause of SWS.100 CEREBROVASCULAR DISORDERS ICC is seen commonly in certain disorders with a primarily vascular mechanism. These include disorders where chronic ischaemia is a probable mechanism, such as SWS or vein of Galen aneurysm, and disorders of the microvasculature, such as COL4A1-related disease. As noted above, mutations in SAMHD1 are associated with cerebral large artery disease and a spectrum of cerebrovascular complications. DOWN SYNDROME Basal ganglia calcification is not uncommon in Down syndrome, and the frequency seems to increase with age.101 OTHER REPORTED DISORDERS ASSOCIATED WITH ICC There are a number of other rare genetic or non-genetic disorders, in which ICC may be seen (Table II), and at least 17 reports of familial disorders for which the genetic basis has yet to be determined (Table I). Some of these have characteristic and striking phenotypes, whereas others demonstrate rather non-specific features. Review

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SUMMARY Intracranial calcification is a common finding on neuroimaging in paediatric neurology practice. In approximately half of all cases the calcification occurs in the damaged, neoplastic, or malformed brain. For the large number of other disorders in which ICC occurs, no common pathogenetic mechanism can be suggested. Congenital infection, particularly with CMV, accounts for a significant proportion of all cases. However, some genetic diseases, in particular AGS, BLC, and RNASET2-related disease, may mimic congenital infection; therefore, a full consideration of the radiological and clinical features is necessary before concluding that congenital infection is the cause. In some disorders calcification is a universal finding, in others a frequent occurrence, and in some only an occasional

finding. Characteristic patterns of calcification are seen in a number of conditions, and a systematic approach to the identification and description of the radiological findings, taken together in the context of the clinical scenario, allows a diagnosis to be made in many cases. Nonetheless, there remain a number of presumed genetic disorders associated with ICC for which the underlying molecular cause has not yet been identified. A CK N O W L E D G E M E N T S We are very grateful to the affected families for their involvement in our research. YJ Crow acknowledges the Manchester National Institute for Health Research Biomedical Research Centre. This work has received support from the Great Ormond Street Hospital Children’s Charity and from the Newlife Foundation.

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