Cerebellopontine calcification: a new entity of idiopathic intracranial calcification?
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- Saito, Y., Shibuya, M., Hayashi, M. et al. Acta Neuropathol (2005) 110: 77. doi:10.1007/s00401-005-1011-y
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We report the autopsy case of a 40-year-old woman with severe intellectual and motor disabilities, who showed calcification in the cerebellum and pons but not in the basal ganglia on CT scan, and died of intracranial hemorrhage due to intractable hypertension. At autopsy, numerous calcium deposits were noted in the cerebellar cortex, the dentate nucleus, the cerebellar white matter and the ventral pons. These deposits were distributed both in the neuropil and the white matter, but rarely within the arterial walls or in contact with capillaries. This weak relationship between calcification and the blood vessels, in addition to the paucity of basal ganglia calcification, is in contrast to the findings with other disorders involving intracranial calcification, including Fahr’s disease and calcium metabolism disorders. Immunohistochemistry revealed intense staining of calbindin-D28K and parvalbumin at sites of calcium deposits both in the present case and in a case of pseudohypoparathyroidism, whereas these proteins were not localized to calcium deposits in the cerebellum of a Fahr’s disease brain. We propose that the present case may represent a distinct entity among diseases characterized by idiopathic intracranial calcification. In addition, calcium-binding proteins may be involved in the calcification process in some cases with intracranial calcification.
Intracranial calcification, frequently observed in the basal ganglia, accompanies many neurological diseases [4, 11, 14, 15, 18, 25, 35, 37, 42, 44] and calcium metabolism disorders including hypoparathyroidism [10, 12, 29] and pseudohypoparathyroidism . Fahr’s disease is one term used to describe idiopathic cases involving intracranial calcification without any primary disease [26, 27, 39]. In such conditions, basal ganglia calcification (BGC) is pathologically characterized by calcium deposits within or adjacent to the vessel walls, which show no arteriosclerotic changes [14, 28, 38]. Certain diseases with BGC show calcification in other sites of the central nervous system. These include the subcortical white matter [21, 26], the cerebellar cortex and the dentate nucleus [16, 29, 38], and the pons [8, 30]. Microscopically, the calcification in these sites appears the same as seen with BGC. In this report, we describe a patient showing calcification in the cerebellum and pontine nucleus, similarly to some cases of Fahr’s disease  and pseudohypoparathyroidism . However, our patient did not show BGC on a computed tomography (CT) scan, and the calcium deposits appeared to have a rare relationship to the blood vessels, in contrast to the aforementioned disorders with BGC. Calcium-binding proteins (CaBPs) are expressed in some subsets of neurons, and modulate their excitability through buffering the intracellular calcium . A distinct distribution of CaBPs in the cerebellum  and the brainstem , together with the role of CaBPs in the mineralization process of extracerebral organs [9, 17], prompted us to examine the expression of CaBPs at calcification sites of the present case, as well as in Fahr’s disease and pseudohypoparathyroidism brains. We therefore examined the involvement of CaBPs in calcification in the present case and compared it to other disorders with BGC.
Materials and methods
After macroscopic inspection, tissues obtained at autopsy were fixed in 10% buffered formalin, and several regions of the cerebrum, cerebellum, midbrain, pons and medulla oblongata were excised, and embedded in paraffin. Brains from a 54-year-old woman with Fahr’s disease and a 46-year-old woman with pseudohypoparathyroidism were examined as disease controls with the consent of their families. Specimens were sectioned at 4 μm and the sections were stained with hematoxylin and eosin, Klüver-Barrera and von Kossa staining. To characterize the nature and distribution of calcium deposits, immunohistochemical analyses were performed on serial sections of the cerebral cortex, lenticulate nucleus, and the cerebellar cortex with the dentate nucleus and pons, using mouse monoclonal antibodies against glial fibrillary acidic protein (GFAP) (Dako Cytomation, Carpinteria, CA), CD34 (Nichirei, Tokyo, Japan), calbindin-D28K (Sigma-Aldrich, St. Louis, MO), and parvalbumin (Sigma-Aldrich). The sections were deparaffinized, immersed in 1% hydrogen peroxide, and rinsed with TRIS-buffered saline (pH 7.6). Microwave treatment was performed to retrieve each antigen. The sections were incubated with the primary antibodies (GFAP 1:100, CD34 prediluted by the manufacturer, calbindin-D28 K 1:100, parvalbumin 1:100) for 48 hours at 4 °C. Antibody binding was visualized by the avidin-biotin-peroxidase method following the manufacturer’s protocol (Nichirei).
General autopsy findings
The lungs demonstrated multiple bullae. Occasional glomerular sclerosis was present in the kidney. Parathyroid glands were normal in size and histological appearance. A calculus of 7×5×5 cm was present in the vagina. Hypertension-related thickening of the arterial media was found in the heart, kidney, pancreas, and brain. Arteriosclerotic change was not evident in any organs.
Gross pathological findings of the brain
The brain was small and weighed 710 g before fixation. The cerebral cortex was atrophied with occipital predominance. Hemorrhage from the left thalamus penetrated into the lateral ventricle and occupied the whole ventricular system (Fig. 1C). Another focal hemorrhage was serially observed from the ventral midbrain to the rostral pontine tegmentum. Otherwise no abnormality was noted in the cerebellum or the brainstem. Calcification was not discernible on macroscopic examination.
Microscopic findings of the brain
Since massive hemorrhage devastated the left cerebral hemisphere, only the right cerebral hemisphere was subjected to reliable histological observation. In the cerebral cortex, marked loss of neurons with gliosis was noted in the occipital lobe. Myelin loss and a decrease in volume were noted in the periventricular white matter at the posterior horn of the lateral ventricle. Several small calcium concretions were observed in the periventricular white matter (Fig. 1D) and in the deep layers of the temporal cortex, but these had no relationship to the vessels, in contrast to the aggregation of mineral deposits along the capillaries in the same regions of the Fahr’s disease (Fig. 1E) and pseudohypoparathyroidism brains. In the basal ganglia, neuronal loss and gliosis were prominent in the globus pallidus. A few small calcium deposits were present in the thickened arterial media (Fig. 1F), whereas vascular calcification was prominent and accompanied with parenchymal spherites in the disease controls (Fig. 1G). A lacunae infarct was observed in the lateral putamen with infiltrating macrophages.
Immunoreactivities in calcium deposits for calcium-binding proteins (− absent, ± equivocal, + weak, ++ moderate, +++ intense, DN dentate nucleus, N lacking calcium deposits, WM white matter)
Some brain lesions in the reported case may have resulted from an intrauterine hypoxia, and from the accompanying hypertension. These include the neuronal loss and/or gliosis in the cerebral cortex, the periventricular white matter, and the basal ganglia. Such pathological changes may have caused the profound intellectual and motor disabilities, as well as epileptic seizures of the present patient. The small number of calcium deposits in these areas may be secondary to the destructive insults. However, the calcifications in the cerebellum and the pons could not be explained by the above complications, because: (1) the calcification emerged on CT scan during adulthood, (2) neurons and other structures adjacent to the deposits were not damaged in these areas, and (3) the neuronal loss in the cerebellar cortex, possibly secondary to an hypoxic event, was marked at the periphery of the cerebellar hemispheres, whereas the calcification was prominent at the folia located deep within the hemispheres.
Disorders showing calcification in the cerebellum and/or pons
Cockayne syndrome 
Tuberous sclerosis 
Congenital anomalies 
Krabbe disease 
Cerebrotendinous xanthomatosis 
Central lupus 
Lead intoxication 
Fahr’s disease 
Hypoparathyroidism/ Pseudohypoparathyroidism 
Multifocal necrotizing leukoencephalopathy 
Aicardi-Goutieres syndrome 
To explore the pathogenic mechanism of calcification in the present case, we performed immunohistochemistry to examine the distribution and expression of CaBPs. Interestingly, calbindin-D28K and parvalbumin co-localized with the calcium concretions. We assume that this result was not artifactual, based on the variability of staining intensity amongst brain regions, and the absence of immunostaining in the cerebellum of the Fahr’s disease brain, as well as the lack of immunostaining with other mouse monoclonal antibodies against CD34 and GFAP. CaBPs in the cell bodies and neurites of the cerebellar and pontine neurons might be involved in the calcification process that is not related to the blood vessels. However, the presence of CaBPs in the calcium deposits in the disease-control basal ganglia, as well as in the cerebellum in the case of pseudohypoparathyroidism, suggests that this process is not specific to the present case. Further investigations are necessary to elucidate the involvement of CaBPs during intracranial calcification.
A report by Puvanendran and Wong  described juvenile hypertension in siblings with idiopathic BGC. The significance of hypertension in the present case remains unknown, but this complication might imply a common pathophysiology among certain cases with intracranial calcifications.
In conclusion, we reported a patient with pontocerebellar calcification. The calcium deposits were characteristic in their anatomical distribution and in the paucity of relationship to the blood vessels. Although the pathomechanism of calcification remains unclear, this type of calcification may represent a distinct entity among diseases involving intracranial calcification.