Immunohistochemical examination on intracranial calcification in neurodegenerative diseases

Fahr-type calcification is a relatively common finding in the elderly, and in younger patients with Alzheimer's disease, calcification in the basal ganglia is not uncommon. However, as far as we know, an immunohistochemical study of intracranial calcification in neurodegenerative diseases has not been performed. In this study, we examined intracranial calcification of the basal ganglia and cerebellum with antibodies against noncollagenous bone matrix proteins. Nineteen brains were employed. The diagnoses were diffuse neurofibrillary tangles with calcification in five, Alzheimer's disease in five, Pick's disease in one, progressive supranuclear palsy in one, Parkinson's disease in one, and six controls. By conventional histology, three patterns of calcium (Ca) deposition were recognized: diffuse deposition within the tunica media of small and medium-sized vessels (type 1 deposition), free spherical or lobulated concretions (type 2 deposition) in the parenchyma, and rows of small calcospherites lying along capillaries (type 3 deposition). Type 3 deposition is relatively rare, and may be a hallmark of severe intracranial calcification. Immunohistochemistry demonstrated that osteopontin was present diffusely in all Ca deposition types. Osteocalcin was present chiefly in the peripheral region of type 2 and 3 depositions, as well as in only the rims of type 1 deposition. Bone sialoprotein and osteonectin were found only in the core portions of type 2 and 3 depositions. In brief, type 1 deposition shows a different staining pattern from type 2 and 3. Different Ca deposition patterns of noncollagenous bone matrix proteins may suggest their separate roles in the pathogenesis of intracranial calcification.     

Intracranial calcification in early infantile Krabbe disease: nothing new under the sun

We report the cases of three children, one male and two females, with a diagnosis of early infantile Krabbe disease demonstrating intracranial calcification on computed tomography (CT). The pattern of calcification was similar in all individuals and involved the internal capsule and cerebral white matter. The presence of calcification caused some diagnostic confusion in what was otherwise a typical clinical and radiological presentation. This finding is not new and has previously been described in publications from the 1980s and 1990s reporting the CT and magnetic resonance imaging appearances of Krabbe disease. With increasing use of magnetic resonance as the first imaging modality for investigation of neurological disorders, characteristic CT appearances may be forgotten. This report serves as a reminder that Krabbe disease should be included in the differential diagnosis of disorders causing intracranial calcification.     

A case of idiopathic, symmetrical non-arteriosclerotic, intracerebral calcification (Fahr's disease) associated with M-proteinemia, followed by multiple myeloma]

We described a 41-year-old woman with idiopathic, symmetrical, non-arteriosclerotic, intracerebral calcification (Fahr's disease), associated with multiple myeloma. CT scans revealed severe calcification in the basal ganglia, floors of cortices, subcortical white matter, brainstem and cerebellum without calcification in the spinal cord. Cerebral angiography showed no evidence of arteriosclerosis. The cerebral blood flow measured by SPECT, parathyroid function and calcium metabolism were within normal range. The initial symptom was dystonia and spasticity in the left leg, when she was 30 years old, followed by gait disturbance, speech impairment, micrographia and dementia. M-proteinemia was pointed out when she 32 years old. M-proteinemia, which was due to primary benign monoclonal immunoglobulinemia (PBMI), made progress slowly, followed by multiple myeloma when she was 40 years old. Periodical CT scans revealed that the intracerebral calcification had worsened gradually through 8 years. Neurological abnormality had also progressed slowly. In literature, there has not been any report about Fahr's disease associated with PBMI and multiple myeloma. Our present study is the first to radiologically prove that the intracerebral calcification in Fahr's disease progresses gradually through its course.     

Lack of progression of brain atrophy in Aicardi-Goutières syndrome

Aicardi-Goutières syndrome is a severe and progressive familial encephalopathy that is characterized by acquired microcephaly, intracranial calcification (mainly of the basal ganglia), signs of white matter disease, and chronic lymphocytosis with elevated levels of interferon-alpha in the cerebrospinal fluid in the absence of other evidence of infection. Although the degree of calcification and the severity of brain atrophy are variable, typically the brain lesions appear to progress on successive examinations. In this article a 4-year-old male patient with Aicardi-Goutières syndrome who manifested the typical neurologic signs of the disease was re-evaluated. The evaluation revealed, on successive cranial computed tomography and magnetic resonance imaging scans, increasing calcification with remarkable reduction of brain atrophy. To the best of our knowledge, there is only one previously mentioned study of a 4-year-old female patient with progressive features of Aicardi-Goutières syndrome, including intracranial calcification, who displayed a lack of progression of brain atrophy at MRI scan.     

Computed tomography of Sturge-Weber disease.

Findings in computed tomography (CT) with or without contrast infusion were analyzed in 8 patients with Sturge-Weber disease. From the extent of calcification in the CT, Sturge-Weber disease can be classified into two types, localized and diffuse. The extent of calcification or cortical atrophy is predictable, if it can be shown that enhanced areas in contrast infusion CT truly represent leptomeningeal angiomatosis. Thus, using enhanced CT, the capacity of prediciton as to whether the patient will have a localized or diffuse type of disease will be possible with further observations.     

Brain calcification in hypoxic-ischemic lesions: an autopsy review

Calcification of ischemic lesions in a child's brain is well recognized by pathologists; however, clinicians and radiologists usually associate cerebral calcification with infections, particularly the TORCH organisms. We illustrate this phenomenon in a 5-month-old infant with extensive, calcified, multicystic encephalomalacia without evidence of a cerebral infection. In order to ascertain the incidence of cerebral calcification in pure hypoxic-ischemic lesions, we retrospectively analyzed 486 consecutive autopsies. Ninety-nine patients had histologic evidence of cerebral hypoxic-ischemic lesions and hypoxia or ischemia. Thirty-nine of these patients displayed microscopic calcification; 23 patients had slight, 12 had minor, and 4 had prominent calcifications. Prominent calcification lesions were large enough to be detected by routine radiologic methods. Correlations between degree of calcification and the underlying disease process and between the gestational age and the length of survival were not statistically significant. This study illustrates the very frequent occurrence of brain calcification in ischemic brain lesions in children. It is necessary to include this diagnosis in the differential diagnosis of cerebral calcification.     

Matrix Gla-protein: the calcification inhibitor in need of vitamin K

Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.     

Nephrogenic diabetes insipidus: a rare cause of intracranial calcification in children

Causes of intracranial calcification in children are numerous. This article describes an unusual cause of intracranial calcification and white matter changes in a child, namely, nephrogenic diabetes insipidus. A 4-year-old boy presented with history of polyuria, polydipsia, failure to thrive, and developmental delay. On examination, he had mild dysmorphic features and spastic paraparesis. Evaluation showed findings suggestive of nephrogenic diabetes insipidus. Computed tomography and magnetic resonance imaging revealed calcification and signal changes in the frontal and parietal subcortical white matter and gray white junction in the parietal and occipital lobes. The involvement of the white matter, in addition to the calcification in this disease, is stressed because it may predict the neurologic outcome.     

Cerebellopontine calcification: a new entity of idiopathic intracranial calcification?

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 Fahrs 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 Fahrs 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.     

Recognizable phenotypes associated with intracranial calcification

Aim In this observational study, we adopted a systematic approach to the radiological phenotyping of disorders associated with intracranial calcification, with the aim of determining if characteristic patterns could be defined as an aid to the future diagnosis of known conditions and the identification of new disorders. Method A cranial imaging‐based scoring system was devised using both computed tomography and magnetic resonance imaging data. Patients were grouped into diagnostic categories where a definitive molecular diagnosis was known, or where the clinical and radiological features suggested a specific diagnosis. For patients in whom the diagnosis was unknown, subgroups were defined according to shared radiological features. Results Data on 244 scans from 119 patients were analysed. A specific diagnosis was available for 59 patients (31males, 28 females; median age 50mo, range 1wk to 54y). These were as follows (number of patients in brackets): Aicardi–Goutières syndrome (33), cerebroretinal microangiopathy with calcification and cysts (10), band‐like calcification with simplified gyration and polymicrogyria (6), COL4A1‐related disease (3), Degos disease (2), Krabbe disease (2), Alexander disease (1), mitochondrial disease (1), and tetrasomy 15 (1). In 60 patients the aetiology was unknown. Within this group, subsets demonstrating shared characteristics suggestive of a specific calcification phenotype could be identified. Interpretation This study confirms the value of a systematic approach to radiological phenotyping of disorders associated with intracranial calcification.     

Sturge-Weber-Dimitri disease without facial nevus

A patient with Sturge-Weber-Dimitri disease presented with intractable seizures and progressive intellectual deterioration. There was no facial nevus or focal neurologic abnormality. CT disclosed bilateral calcification in a parieto-occipital gyral pattern. Histopathology of the brain revealed extensive calcification of vessel wall in parieto-occipital cortices.     

The ultrastructure of Sturge-Weber disease

Summary Five infantile and one adult case of Sturge-Weber disease were studied pathologically. The calcification occurring under the leptomeningeal angiomatosis increased with advancing age. Light and electron microscopy of two cases showed the smallest, and therefore possibly the earliest, calcifications occurred in perithelial cells. It is hypothesized the cause of calcification is anoxic injury to endothelial, perithelial and possibly glial mitochondria due to stasis and abnormal vessel permeability in the cerebral vessels composing the Sturge-Weber angioma.     

Fahr’s disease: variable presentations in a family

Fahr’s disease or Striato-pallido-dentate calcification is a well-defined entity with familial or sporadic presentation and approximately two-thirds of the patients are symptomatic. Herein, we report on different manifestations and neuroimaging of six symptomatic members of a family with Fahr’s disease. It is significant that three symptom-free members of this family also had brain calcification on brain CT scan. The patients’ symptoms had started at different ages with diverse manifestations. The manifestations included extrapyramidal signs, behavioral abnormalities, memory deficits, atonic type of seizure, and ataxia. In further generations, symptoms started earlier.     

A case of pseudohypoparathyroidism with intracerebral calcification

Intracerebral calcifications, especially in the basal ganglia, are observed in many kinds of diseases. A 41-year-old man is reported, who suffered from an acute epidural hematoma and underwent surgery to remove the hematoma. We detected very extensive intracerebral calcification on CT. Laboratory findings revealed hypocalcemia and hyperphosphatemia. General physical examination revealed characteristics typical of pseudohypoparathyroidism. The patient was diagnosed as having pseudohypoparathyroidism type I by the Ellsworth-Howard test. Since the advent of CT, the incidence of basal ganglia calcification has increased. CT is 5 to 15 times more sensitive than skull radiography in the detection of intracerebral calcification. Although many pathological states can cause basal ganglia calcification, most of the calcifications which are recognized on CT scans are physiological. But in cases in which basal ganglia calcifications are recognized also on plain radiographs, various kinds of symptoms including ones of basal ganglia origin are often recognized, and calcifications often extend to regions other than basal ganglia, eg. cerebellum, thalamus, etc. Pseudohypoparathyroidism is a rare disease which presents hypocalcemia, some characteristic physical appearances, and dementia. It is important to decide whether further examinations are necessary or not, when basal ganglia calcification is recognized incidentally on CT scan.     

Alexander disease with periventricular calcification: a novel mutation of the GFAP gene

Alexander disease is a rare neurodegenerative leucoencephalopathy caused by de novo mutations in the GFAP gene. Infantile, juvenile, and adult subtypes have been described and the clinical and radiological phenotypes are broad. Here we report on a single case of juvenile-onset Alexander disease associated with a novel frameshift mutation in the GFAP gene. The 8-year-old male patient had a relatively mild clinical phenotype characterized by dystonia, intermittent episodes of raised intracranial pressure, and characteristic radiological changes. He also presented with the additional and to our knowledge previously unreported, neuroimaging finding of periventricular calcification. We postulate that in children with leucoencephalopathy and periventricular calcification of undetermined aetiology, the diagnosis of Alexander disease should be considered. If the magnetic resonance imaging findings are compatible with Alexander disease, then DNA analysis of the GFAP gene should be performed even if the full criteria for a neuroradiological diagnosis are not met.     

Polyzystische lipomembranöse Osteodysplasie mit sklerosierender Leukenzephalopathie

A 32-year-old patient presented with presenile dementia syndrome and complex-partial seizures. The dementia was preceded by recurrent bone pain which led to surgical intervention for ossear cysts. Computed tomography revealed intracerebral calcification and marked brain atrophy. Clinical, radiological, genetic, and histopathological features of PLOSL disease are discussed in the differential diagnosis of presenile dementia and basal ganglia calcification.     

Pediatric intervertebral disk calcification in childhood: three case reports and review of literature

Introduction  Intervertebral disk calcification is a rare childhood disease. The etiology of disk calcification in children remains unclear. Case reports  We report three cases of children with cervical disk calcification. Their clinical manifestations are very different. The first patient mainly had a neurological deficiency. The second had neck pain and muscular deficit of the left musculus deltoideus. The third had isolated strong neck pain. By presenting these three cases, we want to recall the different symptoms that correspond to this disease and discuss the decisions to be made in regard to radiological investigation and treatment. Discussion  Healing takes place spontaneously after several days, and the calcifications disappears after about 6 months after a stage of fragmentation. Conservative treatment by immobilization of the spine and analgesic therapy are sufficient. Operative treatment should be reserved for severe radicular pain or for significant and persistent sensorimotor deficits from either root or spinal cord compression.     

A case of Fahr's disease presenting "diffuse neurofibrillary tangles with calcification"]

77-year-old woman presented memory disturbance, hallucination, and personality change since the summer of 1988. Laboratory findings revealed normal serum Ca, P, HS-PTH levels and Ellsworth-Howard test was intact. Neuroradiological studies disclosed calcification in the dentate nucleus, putamen, globus pallidus and thalamus. We made a diagnosis of Fahr's disease. During the follow-up period of 13 years, brain MRI showed gradual atrophy in temporal lobes. This case was characterized by the clinical and neuroradiological findings of "diffuse neurofibrillary tangles with calcification: DNTC". We discussed the relations of Fahr's disease and DNTC in the literatures. From our long time observation of this case, we suggest that Fahr's disease includes DNTC.     

A case of progressive familial encephalopathy in infancy with calcification of the basal ganglia and chronic cerebrospinal fluid lymphocytosis

The authors report the ninth case of progressive familial encephalopathy in infancy, with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis, as recently described by Aicardi and Goutieres. The encephalopathy appears during the first year of life with bilateral spasticity, continuing microcephaly, abnormal eye movements, and a rapid course toward a behavioral vegetative state. In every case, there is a mild lymphocytosis in the CSF and brain atrophy with calcification of the lenticular nuclei. No evidence of an infectious disease has been discovered. This syndrome constitutes a distinct type of leukodystrophy, transmitted as an autosomal recessive trait. Our case is a reminder that the presence of CSF lymphocytosis in infants, with encephalopathy and calcification of the lenticular nuclei, may be due to genetic degenerative encephalopathy.