Intracranial calcification is a totally nonspecific sign, occurring either as a physiological phenomenon in otherwise normal individuals or in association with a variety of disorders. Calcification can be single or multiple, can occur within the brain or adjacent to it, and the foci can vary in shape and size. Precise evaluation of the intracranial calcific deposits is now best achieved by using computed tomography (CT), which allows visualization of extremely fine foci of calcification that go undetected by conventional radiography, localizing them precisely with respect to the cerebral substance and CSF pathways. It has been estimated that calcifications of less than 200 HU in CT attenuation value are usually not visualized on plain radiographs (Patel 1987). As a result, the incidence figures for both normal and abnormal intracranial calcifications have risen considerably since the advent of CT (Becker et al. 1977). In the pre-CT/MRI era, the emphasis was on the radiographic appearance of intracranial calcifications, whether tubular and curvilinear (vascular lesions), ring-like (cysts, tumors), or peripheral and concave (subdural hematomas). Although these radiographic signs retain much of their value, a definite diagnosis is now seldom achieved without the use of a cross-sectional imaging modality.
Pathologic calcifications occur in children with a frequency of about 1.6%, the commonest being related to neoplasms (43%), phakomatoses (20%), and infections (12%) (Kendall and Cavanagh 1986). Additional causes include acute brain injury, vascular malformations, metabolic disorders, subdural hematoma, osteomas or osteochondromas of the cranial bones, and malformation syndromes (Haney et al. 1982; Erdem et al. 1994).
In this section, an overview of the 'physiological' types of intracranial calcification is provided first, followed by a discussion of some significant disorders associated with intracranial calcium deposition. Despite the intrinsic limitation of conventional radiography to localize a lesion within the brain, an attempt has been made to arrange the discussion in an anatomically based approach, and the reader is cautioned against considering conventional radiography an exhaustive imaging modality in this setting, which would be risky.
Physiological Intracranial Calcification. Intracranial calcification devoid of clinical significance is age related, being common in adults and rare in newborns and infants. It has been estimated that the prevalence of calcifications involving the pineal gland and choroid plexus is about 2% up to the age of 8 years, with a 5-fold increase by the age of 15 years (Kendall and Cavanagh 1986). As a consequence, intracranial calcification in the pediatric population is often associated with the presence of a disease state. Common sites for physiological intracranial calcification include choroid plexus, basal ganglia, dura of falx and tentorium, pineal gland, habenula, petroclinoid ligament, interclinoid ligament, and pacchionian granulations. The choroid plexus is often calcified in the normal adult population, most commonly in the atrium of the lateral ventricle (Modic et al. 1980). However, calcified choroid plexus can be observed in normal infants 3 years of age or older. Radiographically, they appear as symmetrical, granular or curvilinear calcifications, usually smaller than 15 mm in diameter, projecting 20-30 mm away from the midline on the PA view, behind and slightly below the pineal gland on the lateral view. Calcific deposits larger than 15 mm and more irregular and asymmetrical may be related to the presence of a choroid plexus papillo-ma. Calcification of the basal ganglia, often bilateral and symmetrical, is observed on approximately 0.7%
of CT scans as an incidental finding (plain radiograms usually fail to reveal basal ganglionic calcifications). The globus pallidus is the most common site (Koller et al. 1979; Harrington et al. 1981). These incidental calcifications are usually asymptomatic and cannot be linked with any clearly identifiable etiology, especially in patients over 60 years of age. Calcification of the falx or tentorium occurs in about 10% of adults in the normal population, but is occasionally seen as early as the 3rd year of life. On pos-teroanterior radiograms the calcified falx appears as a thin, midline streak of calcific density in the frontal area, whereas the calcified tentorium appears as a dual streak-like calcific bands in the shape of an inverted 'V' (Kendall and Cavanagh 1986). The pineal gland undergoes calcification in about two-thirds of the normal adult population. Foci of pineal calcification can be seen in children older than 10 years of age, whereas they are rare before the age of 6 years. Punctate or ring-like calcifications smaller than 10 mm in diameter are found in the midline 3-4 cm posterior to the dorsum sellae on lateral radiograms. Foci of calcification that are larger than 10 mm or displaced away from the midline suggest a pineal neoplasm, such as a teratoma or a pinealoma. Calcification of the habenula occurs in about one-third of the adult population, occasionally beginning in childhood after the age of 10 years. It appears radi-ographically as a C-shaped calcification located in the midline, slightly above and 4-6 mm anterior to the pineal gland. The interclinoid ligament is frequently calcified (sellar bridging) in otherwise normal individuals. Calcification of the petroclinoid ligament can be seen as a calcific band extending from the posterior clinoid to the apex of petrous bone as early as 5 years of age. Calcification of the pacchionian granulations may appear as small flecks located adjacent to the sagittal or coronal suture in children older than 10 years of age.
Calcification of the Basal Ganglia. Calcification of the basal ganglia occurs with many medical conditions, including TORCH and other infectious diseases, vascular disorders (birth anoxia,hemorrhage),toxic and metabolic disorders (carbon monoxide intoxication, lead encephalopathy, radiation therapy, hypopara-thyroidism, pseudohypoparathyroidism, hyperpara-thyroidism, hypothyroidism, and lipoid proteinosis) (Kauffman et al. 1992; Fulup and Zeifer 1991; Kowd-ley et al. 1999; McLeod et al. 1989; Lee and Suh 1977; Margolin et al. 1980; Reyes et al. 1986) (Fig. 1.45 a,b). In addition, it occurs with several genetic disorders, including Cockayne syndrome, oculo-dento-osseous
dysplasia, Fahr syndrome,Down syndrome, tuberous sclerosis, pseudo-TORCH syndrome, Aicardi-Gou-tieres syndrome, Kearns-Sayre syndrome, carbonic anhydrase II deficiency, and COFS syndrome (Linna et al. 1982). CT scanning reveals calcium deposition in the basal ganglia (striatum and pallidum) in about 50% of patients with Cockayne syndrome (Jin et al. 1979; Houston et al. 1982). The dentate nuclei of the cerebellum and the cortex of the brain are also frequently involved. Microcephaly and patchy demyeli-nation, often severe, of the subcortical white matter are additional neuropathologic findings (Gorlin et al.
2001b). In oculo-dento-osseous dysplasia (oculo-den-to-digital dysplasia, OMIM 164200), a narrow nose with hypoplastic alae and thin nostrils, microcornea with iris anomalies, postaxial syndactyly and/or camptodactyly, hypoplasia/aplasia of the 5th fingers and toes, and enamel hypoplasia are leading features (Meyer-Schwickerath et al. 1957). Additional features include short palpebral fissures, epicanthal folds, skull hyperostosis, hypotrichosis, strabismus, glaucoma, orbital hypotelorism, and a variety of neurological symptoms, such as progressive paraparesis, cerebral white matter abnormalities, ataxia, tremor, bladder dysfunction, epilepsy, migraine, and learning disabilities (Beighton et al. 1979; Fara and Gorlin 1981; Gutmann et al. 1991; Loddenkemper et al. 2002). Calcification occurs in the basal ganglia (Barnard et al. 1981). The syndrome is inherited in an autosomal dominant pattern and is caused by mutation in the connexin-43 gene mapped to 6q21-q23.2 (Gladwin et al. 1997; Boyadjiev et al. 1999). Approximately half the cases represent fresh mutations, which are probably related to increased paternal age (Jones et al. 1975). Fahr disease (idiopathic basal ganglia calcification, OMIM 213600) is a neurodegenerative disorder characterized by widespread brain calcification and a variety of neurological and cognitive manifestations, including progressive dystonia, dys-arthria, parkinsonism, ataxia, seizures, and dementia. Bilateral, often massive, calcium deposits occur primarily in the strio-pallido-dentate system, but can be distributed throughout the cerebral cortex, thalamus and subthalamus, red nucleus, cerebellum, and internal capsule. Usually the patients are between 30 and 60 years of age at presentation, though some cases manifest during childhood. Mineral deposits occur in the extracellular and extravascular spaces, often around small vessels, and are associated with severe cell loss in the involved areas, demyelination, glial cell proliferation, and absence of signs of inflammation, infections, and intracellular accumulation of metabolic products (Jervis 1954). Brain cell loss results in accumulation of both calcium and iron; hence the designation 'ferrocalcinosis' sometimes used to describe this disorder (Babbitt et al. 1969). However, the reason for calcium deposition remains unknown: it is thought that either a local disruption of the blood-brain barrier or impaired neuronal calcium metabolism may be the cause (Geschwind et al. 1999). The disease is usually transmitted as an autosomal dominant trait (Callender 1995), although instances of presumed autosomal recessive inheritance have been reported (Nyland and Skre 1977; Smits et al. 1983). One gene locus for the dominantly inherited form has been mapped to chromosome 14q (Geschwind et al. 1999). However, lack of linkage to this locus in another affected family (OMIM 606656),in which calcification was inherited independently of neurological symptoms, suggests genetic heterogeneity (Brodaty et al. 2002). Pseudo-TORCH syndrome (pseudotoxoplasmosis syndrome, OMIM 251290) is a familial disorder in which some features closely mimic a TORCH infection (microcephaly, mental retardation, and cerebral calcifications) whereas others (absence of chori-oretinopathy, negative serology for TORCH) clearly identify it as a separate entity (Reardon et al. 1994). Inheritance is either autosomal or X-linked recessive (Ishitsu et al. 1985). Aicardi-Goutières syndrome (OMIM 225750) is an early-onset, progressive encephalopathy characterized by microcephaly of postnatal onset (head circumference is normal at birth), extensive calcification of basal ganglia, chronic CSF pleocytosis - which might erroneously suggest an inflammatory condition -, raised interferon alpha in the cerebrospinal fluid, leukodystrophy, and gray matter loss with brain atrophy (Aicardi and Goutières 1984; Mehta et al. 1986). Clinical symptoms include severe psychomotor delay, spasticity, and extrapyramidal signs (Bonnemann and Meinecke 1992). Death usually supervenes in early childhood. Serologic studies for TORCH are negative, and thrombocytopenia with purpuric rash does not occur. Calcifications are also found in the cerebral cortex, cerebellum, and sylvian fissure. The disorder is transmitted as an autosomal recessive trait. One gene locus has been mapped to chromosome 3p21 (Crow et al. 2000), but locus heterogeneity has been recognized. Kearns-Sayre syndrome (oculo-cranio-somatic syndrome, OMIM 530000) is an encephalo-myopathy caused by various mitochondrial DNA deletions and characterized by ophthalmoplegia, pigmentary degeneration of retina, and cardiomyopathy as its leading features (Kearns 1965; Seigel et al. 1979; Robertson et al. 1979; Barshop et al. 2000). Less consistently present features include weakness of several muscles in the face, pharynx, trunk and extremity, deafness, small stature, electroencephalographic changes, and markedly increased CSF protein. Brain abnormalities include cerebellar and brain stem atrophy and basal ganglia calcification.
Calcification of the Falx or Tentorium. Among patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome, OMIM 109400), lamellar calcification of the falx cerebri is found in 55-95 %, whereas the tentorium is calcified in 20-40 %, the diaphragma sellae
in 60-80%, and the petroclinoid ligament in 20% (Ratcliffe et al. 1995). The skull is macrocephalic in about 80% of cases, with frontal and parietal bossing, but appears to be in proportion with the patient's height (Bale et al. 1991). Bilamellar calcification of the falx cerebri is a major diagnostic criterion, whereas macrocephaly and frontal bossing are minor diagnostic criteria (Kimonis et al. 1997). It is worth noting that calcified brain neoplasms, such as menin-gioma and craniopharyngioma, and radiation therapy are also possible sources of intracranial calcification in patients with Gorlin syndrome.
Sellar or Parasellar Calcification. Pathologic calcifications in this area may be related to a number of conditions, including vascular anomalies (aneurysm of internal carotid artery, circle of Willis, or basilar artery; atherosclerosis of internal carotid artery; AV malformation), infections (tuberculous meningitis, cysticercosis), and neoplasms (craniopharyngioma, chordoma, ectopic pinealoma or teratoma, menin-gioma, optic chiasm glioma, osteochondroma, chon-droma, osteoma, pituitary adenoma) (Reeder 1993; O'Neill et al. 1980; Tamaki et al. 2000) (Fig. 1.46). Typically, calcifications associated with giant aneurysms or AV malformations have a curvilinear appearance. Tuberculous meningitis can cause single or multiple small flecks of calcification involving the chiasmatic cistern or, more rarely, the meninges. Occasionally, a nodular or eggshell pattern of calcification is seen in association with tuberculomas. Craniopharyngioma exhibits a variable pattern of calcification (irregular, patchy, eggshell) in up to 80 %, often associated with sellar enlargement or erosion. Clival chordoma frequently displays calcified areas in the midline, within or posterior to the clivus, with extensive destruction of sella and clivus.
Periventricular Calcifications. Various neurotropic infectious diseases, notably those grouped together under the designation of TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2), are primary causes of subependymal calcification in the young infant, sometimes accompanied by bizarre ventricular configurations and prominent periventricular cystic encephalomalacia (Grant et al. 1985). Cytomegalovirus (CMV) is the most common cause of congenital and perinatal viral infections throughout the world, occurring in 0.52.5% of all live births (Alford et al. 1990). Approximately 15 % of these manifest the full disease during the neonatal period, whereas another 10-15% develop neurological or developmental abnormalities symptoms in the first few months of life (Griffiths 2002). The virus is transmitted from the mother to the fetus through the placenta, and causes a systemic viral fetal infection, which is most severe if contracted during early pregnancy. Affected newborns are often delivered prematurely, and manifest at birth with severe growth deficiency (35%), pneumonitis (25%), hepatosplenomegaly (90%), thrombocytopenia (70%) and associated purpuric rash, jaundice (50%), and hemolytic anemia (50%). Because of the necrotizing nature of the meningoencephalitis, common sequelae include microcephaly (40%), periventricular calcifications (25%), mental retardation, seizures, sen-sorineural hearing loss, and motor deficits (Alpert and Plotkin 1986; Stagno et al. 1986). In severe cases, lissencephaly with a thin cortex, cerebellar hypopla-sia, and marked ventriculomegaly are features seen on cross-sectional imaging examinations. Choriore-tinitis resulting in optic atrophy and obstructive hy-drocephalus may also occur. Brain calcifications are usually widely distributed in the periventricular areas and appear as numerous small flecks or a fine subependymal layer of calcium outlining the ventricles. The reason for this preferential location of brain calcifications is disputed. A direct cytopathic effect of the virus on the rapidly growing cells of the germinal matrix and a primary vascular target for the virus, resulting in brain ischemia, have both been postulated (Marques Dias 1984). Toxoplasmosis, a protozoal infection caused by Toxoplasma gondii, is also very common, occurring as a primary maternal infection in about 6 in 1,000 pregnancies in the United States (Sever et al. 1988). About half of these pregnancies culminate in the birth of a congenitally infected baby, 75% of whom are asymptomatic while 10% are severely affected and 10% are stillborn. As in the case of CMV infection,the earlier the time of infection the more severe the infection. Prematurity occurs in about 25%, mental retardation in 80%, seizures or other neurological symptoms in 70 %, chorioretinitis in 50%, sensorineural hearing loss in 15%, and hydrocephalus and microcephaly each in 5% of cases. Additional symptoms include hepatosplenomegaly, liver dysfunction, thrombocytopenia, and petechial rash. Unlike cytomegalovirus infection, congenital toxoplasmosis is seldom accompanied by cortical dysplasia (Barkovich 1996). Intracranial calcifications are seen in about 10% of cases, being located in the periventricular area or, less commonly, in the basal ganglia, choroid plexus, and meninges (Frenkel 1985; Feldman 1974; Chowdhury 1986). Rubella em-bryopathy is now extremely rare in developed countries, because of extensive vaccination and maternal screening programs. The disease is most severe if the virus affects the fetus early during gestation, manifesting with lethargy, hypotonia, a bulging fontanel, cataracts, glaucoma, hearing loss, psychomotor retardation, seizures, and cardiac malformations (Nu-mazaki and Fujikawa 2003). Brain tissue loss eventually results in ventriculomegaly with microcephaly. Microphthalmia and chorioretinitis are common. Spotty or irregular periventricular calcifications, often localized in areas of liquefactive necrosis and gliosis, are commonly seen (Harwood-Nash et al. 1970; Rowen et al. 1972). When the fetus is infected during the last trimester of gestation the disease is usually benign. Perinatal herpes simplex virus infection is usually caused by exposure of the baby to maternal type II genital herpetic lesions as he/she passes through the birth canal during delivery. Infections occurring in utero often result in fatal disease. Symptoms usually develop during the 1st month after birth and may include cyanosis,jaundice,fever,respi-ratory distress, or meningoencephalitis manifesting with lethargy, fever, and seizures (Noorbehesht et al. 1987). Mental retardation and severe neurological deficits are common sequelae. Loss of brain substance and encephalomalacia of white matter result in severe cerebral atrophy. Calcification may assume a variety of distributions, from a punctate to an extensive gyral pattern (Noorbehesht et al. 1987; Ketonen and Koskieniemi 1983). Tuberous sclerosis (Bourneville-Pringle syndrome, OMIM 191100) is an hamartoneoplastic disorder in which the potential for hamartomatous growth in multiple tissues and organs, including the skin, brain, skeleton, eye, kid-
ney, and heart, results in variable clinical symptoms that are usually progressive with age. The term 'tuberous sclerosis,' which was coined by Bourneville (1880), refers to one of the characteristic lesions of the disease, i.e., cortical brain tubers that subsequently undergo calcification (sclerosis). Mild cases can be overlooked. The classic triad of seizures, mental retardation, and facial angiofibromas represents the other end of the spectrum of severity (Gorlin et al. 2001a). Primary diagnostic criteria in tuberous sclerosis, only one of which is required for the diagnosis, include facial angiofibromas, ungual fibromas, cortical tubers and subependymal hamartomas, multiple renal hamartomas, and fibrous plaques on the forehead (Gomes 1979; Roach et al. 1998). The disease has a prevalence of 1 in 6,000 births and is sporadic in two-thirds of cases (Ponsot and Lyon 1977). Many pedigrees support autosomal dominant inheritance with variable expression (Cassidy et al. 1983; Sybert and Hall 1979; Green et al. 1994). Tuberous sclerosis differs from other autosomal dominant disorders in that no significant parental age effect has been observed in sporadic cases (Sampson et al. 1989). Several instances of gonadal and/or somatic mosaicism have been reported (Wilson and Carter 1978; Verhoef et al. 1999; Kwiatkowska et al. 1999). The disease is genetically heterogeneous, with mutations occurring in the TSC1 gene at 9q34 and the TSC2 gene at 16p13.3 (Fryer et al. 1987; Kandt et al. 1992; Povey et al. 1994). Skin lesions include facial an-giofibromas, hypomelanotic macules, periungual or subungual fibromas, and pedunculated cutaneous nodules or skin tags. Facial angiofibromas are bilat-
eral, pink or reddish lesions involving the cheeks, nasolabial folds, and perioral area (except the upper lip). They occur in 70-85% of cases and usually appear in childhood or adolescence, progressing in severity in subsequent years (Webb et al. 1996). The hypomelanotic macules, leaf-shaped or round in configuration, occur in about 65% of cases and are often present at birth (Monaghan et al. 1981). Periun-gual or subungual fibromas usually appear at puberty and are seen in 90 % of affected individuals older than 30 years. Typical brain lesions include sub-ependymal hamartomas (giant cell astrocytomas) and cortical tubers. These lesions are clearly depicted by MRI. Nodular or stippled areas of calcification within the lesions are detected in about 56% of patients, more commonly in the supratentorial (88 %)
than the infratentorial (12%) location (Ponsot and Lyon 1977; Nixon et al. 1989) (Fig. 1.47). The calcified foci can be bilateral or, less commonly, unilateral and are typically progressive, accounting for about 15% during the 1st year of life, 35% during the first 5 years, and 50-60% by the age of 14 years (Fig. 1.48 a,b). Occasionally, the subependymal lesions obstruct the foramen of Monro, leading to unilateral hydrocephalus. Clinical manifestations of central nervous system involvement include seizures (8090%), mental deficiency (40%), and childhood autism (25-40%). Involvement of the skeleton manifests with typical cyst-like lesions in the phalanges and irregular periosteal new bone formation along the shafts of the metacarpals and metatarsals. Macro-dactyly has been repeatedly reported (Sahoo et al. 2000). Retinal hamartomas are found in approximately 50% of cases, whereas multiple kidney an-giomyolipomas occur in about 60% (van Baal et al. 1989). Multiple renal cysts and renal cell carcinoma are uncommon, each occurring in about 2% of patients (Sampson et al. 1995). Single or multiple cardiac rhabdomyomas (30%), cystic disease of the lung, pulmonary lymphangiomyomatosis, heman-giomas and angiomyolipomas of the liver and spleen (50%), hamartomas of the thyroid, pancreas, and testis, nodular fibrous growth of the oral cavity (35-45%), enamel pitting, and fibrous lesions of the jaw are additional potential manifestations of the disease (Webb and Osborne 1992; Smith et al. 1989; Scully 1981).
Peripheral Cerebral Calcifications. Sturge-Weber syndrome (encephalotrigeminal angiomatosis, OMIM 185300), a congenital disorder occurring only sporadically, is defined as a capillary malformation of the leptomeninges, with or without involvement of the choroid and facial branches of the trigeminal nerve resulting in a facial port wine nevus. The syndrome can be explained by the abnormal persistence of the embryonic vascular plexus that forms during the 6th week of development around the cephalic portion of the neural tube, and it normally disappears by the 9th gestational week. Capillary malformations of the skin may extend from the head and neck to other parts of the body, including upper and lower limbs (Inan and Marcus 1999). Unlike Klippel-Trenaunay-Weber syndrome (OMIM 149000), which is sometimes associated (Nonnenmacher 1955), Sturge-Weber syndrome does not involve lymphatic or venous malformations or regional gigan-tism (except for bony maxilla overgrowth) and macrodactyly, capillary malformations being the sole vascular anomaly. Seizures, either local or generalized, are common manifestations (83%) that often manifest during the early years of life, whereas neurological deficits (65%), glaucoma (60%), and developmental delay (43%) are less frequent (Sujansky and Conradi 1995). Increased cerebral blood flow is detected in the involved cortex prior to the onset of seizures. In contrast, rapid brain hypoperfusion and atrophy, and hence brain impairment, supervene once seizures have occurred (Aylett et al. 1999). Altered hemodynamics within the leptomeningeal malformation results in precipitation of calcium deposits throughout the cortex underlying the pial an-giomatosis, producing the double contoured 'railroad track' gyral calcification. This characteristic pattern of peripheral cortical calcification is usually detected by conventional radiology after the age of 2 years, but can be detected by CT as early as the neonatal period (Kitahara and Maki 1978). Ipsilateral to the involved hemisphere there is calvarial thickening and enlargement of mastoid air cells and paranasal sinuses, resulting in facial asymmetry. Occasionally, bilateral hemispheric involvement is observed (Botshauser et al. 1976).
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