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Basal ganglia calcification is a frequent incidental finding in asymptomatic individuals, and may be considered a normal component of ageing (over 50 years) in up to 20% of asymptomatic patients.

Genetic causes of this condition are termed primary familial brain calcification (PFBC), as opposed to secondary causes of intracranial calcification (with the term primary having the usual implication of an underlying genetic cause).

The term Fahr’s disease is in widespread use, and idiopathic basal ganglia calcification is a another synonym.


Primary forms
Gene
SLC20A2: Solute Carrier Family 20 Member
PDGFRB:  Platelet-Derived Growth Factor Receptor Beta
PDGFB: Platelet-Derived Growth Factor Beta
XPR1: Xenotropic and Polytropic Retrovirus Receptor 1
MYORG: Myogenesis Regulating Glycosidase

Secondary forms
Calcium/phosphorus abnormalities
Idiopathic or secondary hypoparathyroidism
Infections (brucellosis, AIDS, toxoplasmosis, TORCH complex)
Toxic exposure (lead, carbon monoxide)
Autoimmune (SLE)

Other conditions
Pseudohypoparathyroidism
Down's syndrome
Cockayne syndrome I and II
Aicardi-Goutières syndrome
Mitochondrial diseases (MELAS, MERRF); Leigh's syndrome (PDH deficiency)
Coat’s syndrome
Neuroferritinopathy, NBIA

 

Radiology

Calcification is typically bilateral and symmetrical, most frequently located in the basal ganglia, but also present in the dentate nuclei, thalami (posterolateral), brainstem, centrum semiovale, and subcortical white matter. Pathological lesions are usually easily distinguished from age-related physiological calcifications of the basal ganglia by particular features: age related changes are often small and faint, symmetrical and confined to the globus pallidus, whereas the pathological lesions are more diffuse and extensive, and also involve the putamen and dentate nucleus.

On CT scanning, hyperintense lesions on CT images with Hounsfield units (Hu) exceeding an established threshold of 100 Hu are considered to be calcified, whereas haemorrhages usually show less attenuation (<90 Hu) or are isointense to brain tissue.

Calcium is a diamagnetic substance that may appear bright with T1-weighted studies, but, at higher concentrations, the intensity of the signal in calcium becomes less. By contrast, with T2-weighted studies, calcified lesions may appear either hypointense or hyperintense, because of the presence of other minerals in the same areas such as zinc, manganese, iron, and magnesium1.

Susceptibility weighted imaging (SWI) imaging is a sequence with high sensitivity for blood products and iron, and is currently the best MRI sequences to identify calcification, which appears hypointense.  Susceptibility in SWI imaging can be due to haemorrhage, iron, calcification, and gas.

Figure 1. Normal SWI in 53 year old patient

 


 

SWI exploits the magnetic susceptibility differences of various compounds, such as blood, iron, and diamagnetic calcium, which have inherent properties which allow them to serve as sources of MR contrast2.
-Diamagnetic materials have all their electrons paired, and are repelled by a magnetic field. Diamagnetic materials include calcium and oxyhemoglobin.
-Paramagnetic materials have at least one unpaired electron in the system; paramagnetic and ferromagnetic materials are attracted by a magnetic field. 
The paramagnetic deoxyhemoglobin serves as an intrinsic contrast agent on SWI sequences, and is low in signal. This causes magnetic field inhomogeneity due to two effects: a reduction of T2* and a phase difference between the vessel and its surrounding tissue. (This property also forms the basic principle for blood oxygen level dependent functional and venographic imaging).

Paramagnetic substances display positive phase shift in left-handed MR systems such as Siemens magnets. Hence, the phase images are particularly useful for differentiating between paramagnetic susceptibility effects of blood products such as deoxygenated hemoglobin, intracellular methemoglobin, hemosiderin and ferritin (positive shift) and diamagnetic effects of calcium (negative or no shift).

Unfortunately, ferrocalcinosis may lead to confusing signal intensity patterns as even basal ganglia “calcification” is often a mixture of paramagnetic iron and diamagnetic calcium. Basal ganglia calcifications show a paramagnetic susceptibility effect, whereas other calcifications located outside the basal ganglia (such as choroid plexus or dural calcifications) exhibit exclusively a diamagnetic susceptibility effect.

More information on SWI

Functional imaging studies with F-Dopa PET and DAT imaging  have shown variable findings, including normally functioning nigrostriatal pathways, but also findings of both pre- and postsynaptic loss of dopaminergic function in the striatum1.
 

Figure 2. Imaging of PFBC

a. Brain MRI showing T1- hyperintensity in basal ganglia, and marked T2*-GRE hypointensities in the same regions (b).
Brain CT scan showed diffuse symmetric calcifications involving basal ganglia (c), and dentate nucleus (d).

From: Donzuso G, Mostile G, Nicoletti A, Zappia M. Basal ganglia calcifications (Fahr’s syndrome): related conditions and clinical features. Neurol Sci 2019; 40: 2251–63.

 

Neuropathology

PFBC is a disease of the cerebral microvessels, involving the vascular smooth muscles cells and pericytes. Calcifications are observed in the tunica media of medium- and small-calibre arteries, arterioles, and capillaries leading to the obstruction of the lumen.  Reactive astrocytes and microglia accumulate around the calcified deposits, indicating an ongoing inflammatory process.
Histopathological studies showed that calcium is the major element present and it accounts for the radiological appearance of the disease, together with the involvement of several minerals like iron, magnesium, aluminium, and zinc.
Gross examination demonstrates grey discoloration and gritty consistency of the posterior periventricular region, globus pallidus, putamen, and anterior thalamus and mild atrophy of the caudate nucleus, as well as in the cerebral cortex.

Genetics

The first mutations causing PFBC were identified in the SLC20A2 gene, an inorganic phosphate transporter, in 2012. Mutations in SLC20A2 gene are responsible for most cases identified so far and over 40 pathogenic variants have been reported in patients with PFBC.

Subsequently, PFBC mutations have been reported in four additional genes: PDGFRB, PDGFB, XPR1, and MYORG.  PFBC is genetically heterogeneous, with five loci and four genes currently identified3. All the known genetic types are inherited in an autosomal-dominant manner. SLC20A2 encodes the inorganic phosphate transporter, Pit-2, a transmembrane protein associated with phosphate homeostasis in various tissues, including the brain, and its mutations result in a reduction of phosphate transport.

Although penetrance of the imaging phenotype may be 100%, many cases are asymptomatic, suggesting reduced penetrance of the mutations and/or unrecognized clinical symptoms and signs in carriers of mutations1.  In affected families, calcified deposits may be seen in children, suggesting that the pathologic and anatomic changes begin many years before the onset of clinical manifestations

Clinical features

Although PFBC has been described in all age groups, the onset is usually in the fourth to sixth decade. The typical presentation is a progressive movement disorder, psychiatric and cognitive manifestations clinically overlapping with many neurodegenerative diseases (Warren et al., 2002).

Cognitive and psychiatric manifestations:

Neuropsychiatric presentations include psychosis, depression, and irritability/anxiety.
Patients with extensive calcification seem to exhibit a higher frequency of psychiatric disorders than patients with more limited involvement of brain structures; however, the relationship between calcium deposits and clinical symptoms is not well established.

Behavioural problems can include apathy, disinhibition, aggressiveness, obsessive-compulsive, or impulse control disorders3. Cognitive impairment may range from a mild memory and attention deficit to frank dementia of frontal-subcortical type.

Neurological features:

Extrapyramidal symptoms are present in most cases and can be the first manifestation of the disease, with virtually any type of involuntary movement, including rest and action tremor, parkinsonism, dystonia, choreoathetoid movements, myoclonus, and tics.
Spasticity may also be present. Parkinsonism may be commoner in SCL20A2, and PDGFB cases have hyperkinetic movements in 25% of cases1.

Migraine, often with aura, and vertigo are common, and may be the only manifestation for many years. Epilepsy is present in some cases, including a range of seizure types, as well as syncope, stroke, and stroke-like episodes.
Up to a third of patients may be asymptomatic, even at an advanced age, and with extensive calcified areas visible in the neuroimage.

Video 1. Chorea associated with an SLC20A2 mutation

Chorea predominantly involves the left hand, associated with myoclonic jerks.

(vv)Fahr.mp4(tt)

From: Carecchio M, Barzaghi C, Varrasi C, Cantello R, Garavaglia B. Adult-Onset Focal Chorea in Fahr's Disease Resulting From SLC20A2 Mutation: A Novel Phenotype. Mov Disord Clin Pract. 2014 Dec 6;2(1):79-80. doi: 10.1002/mdc3.12114. 

Calcium/phosphorus abnormalities in hypoparathyroidism

Causes include abnormalities in the ratio of calcium to phosphorus, particularly due to parathyroid hormone (PTH) disorders, which include idiopathic or secondary hypoparathyroidism. Idiopathic hypoparathyroidism is an uncommon condition: almost ¾ of patients  showed basal ganglia calcifications on CT scan and its occurrence and progression are associated with low Ca/P ratio

Secondary hypoparathyroidism is a relatively frequent complication of total or subtotal thyroidectomy. Consequently, the most common clinical scenario underlying basal ganglia and dentate nuclei calcifications is secondary hypoparathyroidism due to thyroid surgery with destruction or vascular compromise of parathyroid tissue, and an abnormal Ca/P ratio, leading to hyperphosphatemia and hypocalcaemia. Symptoms due to hypocalcaemia include paraesthesiae, cramps, spasm of carpal and pedal muscles, neuromuscular irritability, and ECG abnormalities such as prolonged QT interval.  A variety of neurological signs and symptoms are found, including seizures, gait disturbances and postural instability, cognitive decline, parkinsonism, and rest tremor.

Infections

Brain infections, such as brucellosis, acquired immune deficiency syndrome (AIDS), toxoplasmosis, but also intrauterine and perinatal congenital infections (toxoplasmosis, rubella, cytomegalovirus, or herpes simplex virus—TORCH complex) may result in brain calcification.

Calcification is one of the most common pathological findings and involves blood vessels of multiple organs, including the brain. Up to a third of HIV-infected children show bilateral and symmetrical basal ganglia calcifications, involving putamen and globus pallidus and are usually not seen before 10 months of age.

Pseudohypoparathyroidism

Brain calcifications can also occur in genetically determined PTH resistance, defined as pseudohypoparathyroidism, in which clinical and laboratorial hypoparathyroidism findings (hypocalcemia, hyperphosphatemia) are associated with normal or high levels of PTH. This condition is associated with seizures, movement disorders with or without cognitive impairment, and psychiatric symptoms together with other clinical features such as short stature and skeletal abnormalities.

Mitochondrial diseases

Mitochondrial disorders may be associated with abnormalities in calcium metabolism and high level of serum lactic acid. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and myoclonic epilepsy with ragged red fibers (MERRF) have been associated with calcification of the basal ganglia.

Neurodegenerative

Neurodegenerative conditions such as neurodegeneration with brain iron accumulation (NBIA) and neuroferritinopathy are associated with basal ganglia calcification due to excess iron storage, neuroinflammation, or cystic degeneration, mainly in the putamen and globus pallidus.

Autoimmune

SLE may be associated with diffuse calcification, including cortex and basal ganglia.

References

1            Donzuso G, Mostile G, Nicoletti A, Zappia M. Basal ganglia calcifications (Fahr’s syndrome): related conditions and clinical features. Neurol Sci 2019; 40: 2251–63.

2            Halefoglu AM, Yousem DM. Susceptibility weighted imaging: Clinical applications and future directions. World J Radiol 2018; 10: 30–45.

3            Quintáns B, Oliveira J, Sobrido MJ. Primary familial brain calcifications, 1st edn. Elsevier B.V., 2018 DOI:10.1016/B978-0-444-63233-3.00020-8.