Background
Fahr’s disease, Bilateral striopallidodentate calcinosis [
1], and
Idiopathic basal ganglia calcification [
2] are three of the more than 30 names used to identify a rare neurodegenerative condition characterized by the presence of bilateral calcification of the basal ganglia and other parts of the brain [
3]. This condition has a wide range of possible clinical manifestations, usually marked by neuropsychiatric symptoms (i.e. dementia, schizophrenia-like psychosis, mood disorders), and extrapiramidal movement disorders [
3]. Fahr was the first author who, despite a few previous case-reports by others [
4,
5], described in 1930 the case of a demented patient with movement disturbances, whose autopsy revealed
vascular non atherosclerotic calcifications in centrum semiovale and striatum [
6].
For years, the terms
Fahr’s disease and
Fahr’s syndrome have been used indistinctly to identify different clinical conditions characterized by basal ganglia calcification. Nowadays, several authors use the term
syndrome referring to clinical cases, symptomatic or not, in which a specific cause can be identified at the basis of brain calcification [
7]. Nevertheless, there is no agreement about the use of the term “Fahr’s syndrome”, since, under this name, are grouped a very wide range of conditions, with different etiologies, pathogeneses, and different clinical phenotypes, raising the question of the real existence of such a syndrome. In fact, a study conducted in 2007 found that among 1569 healthy subjects, 0.8 % presented basal ganglia calcifications at CT scan, apparently without any symptoms, thus inducing the authors to consider them intracranial “physiological” calcifications [
8]. More recently, irrespective of the etiology, Manyam proposed a classification based on the anatomical site in which calcium and other minerals depose, including 1. striopallidodentate calcinosis, 2. bilateral striopallidal (basal ganglia) calcinosis, and 3. bilateral cerebellar calcification [
3]. In this paper we report seven consecutive cases of patients with basal ganglia calcification detected from a series of 750 patients referring to our Clinic for the study of Cognitive Diseases or to our Internal Medicine Ward from January 2003 to December 2013. Our purpose was, in a group of patients with non-genetic forms of basal ganglia calcinosis, to evaluate whether a clinical picture corresponding to neuroimaging could be detected and, consequently, whether the use of the term “syndrome” may be correct.
Conclusions
In the present work we describe the clinical presentation of seven subjects with basal ganglia calcification. By comparing these clinical cases with current Literature we observed that actual studies don’t allow conclusions about real clinical features of basal ganglia calcification, in relation to qualitative and methodological limitations. The only exception is represented by inherited Fahr’s disease, in which the early calcium deposition in nucleus pallidus and striatum is inevitably related to severe, although heterogeneous, clinical manifestations. Moreover, it must be pointed out that the very few anatomical pathology studies show a late neuronal involvement; therefore, it is not possible to relate in any way the morphological findings obtained by CT scan with the real impairment of the anatomic pathways concerned. Several observations can be made considering the seven, heterogeneous, presented cases.
Patient of Case 1, was affected by
strio-pallido-dentate calcinosis. This is probably a case of
Fahr’s disease with severe primitive calcifications, even if a form secondary to cerebrovascular disease cannot be excluded. However, the clinical picture favors the hypothesis of
Late onset Fahr’s disease, since well-structured delusions with emotional involvement are very rare in vascular dementia [
58]. Extrapiramidal disorders developed two years after the first observation: they might represent late symptoms of the disease or side effect of antipsychotic treatment. The disappointing response to this treatment, and the possible development of side effects, are in favour of Fahr’s disease [
44].
Case 2 was affected by
strio-pallidal calcinosis [
3], probably this was a case of Secondary BGC (Basal Ganglia Calcification) due to the previous brain injury. As reported for early onset forms, the predominant symptom was the psychotic disorder. Also mild cognitive impairment is a typical symptom of BGC, even if in early onset type it usually appears later. Unfortunately, no information about the neurologic examination before starting antipsychotic therapy was available; however at the time of evaluation the patient was amimic: in lack of other elements this could suggest a Parkinsonism. Finally, the unsuccessful response and hypersensitivity to antipsychotic therapy supports SBCG diagnosis [
44].
Case 3 presented with a
strio-pallidal calcinosis [
3] too, but the later beginning of the symptoms configures a
late onset idiopathic form, although we don’t actually know the duration of the psychiatric disturbance before the patient was taken in charge. The preponderant symptom was the anxious-depressive syndrome resistant to drugs. The observation of memory deficit suggests the presence of cognitive impairment, even if a complete neuropsychological evaluation was not available. However, the relatively lower impact of cognitive deficit compared with mood disorder is typical of the early onset forms. Besides basal ganglia calcification, the mild atrophy showed at CT scan could explain, at least in part, the cognitive deficits.
Case 4 presented a
strio-pallidal calcinosis [
3], in this case due to a probable secondary BGC. A mood disorder was the prevalent symptom, even if a mild cognitive impairment was also detected. Two probable etiologic elements must be considered: severe hypovitaminosis D with secondary hyperparathyroidism and brain injury. Alteration in calcium/D vitamin metabolism can be at the basis of BGC [
21,
22], but symptoms develop only after the brain injury, which seems to act as a trigger in this case. Probably, the brain injuries accelerated the evolution of the pathology that otherwise would have manifested as a late onset form. Again, the depressive syndrome was resistant to antipsychotic/antidepressant therapy at maximum dose, suggesting that BGC may induce resistance to antidepressant treatment, in addition to cognitive decline (cases 3–4), and head trauma (case 4).
Case 5 presents a
strio-pallido-dentate and occipital
calcinosis [
3], probably of idiopathic origin (Fahr’s disease). Despite a quite extensive calcification, symptoms were really mild, and the diagnosis was incidental. At neuropsychologic evaluation very mild cognitive deficits emerged: this could represent the outset of a
late onset form, commonly characterized by dementia [
46,
47], even if vascular dementia could not be excluded. Finally, BGC can be secondary to the small brain tumor [
30,
31]; usually, gliomas and angiomas are involved, while no association with meningiomas have been reported in literature.
Case 6 presented a
strio-pallidal calcinosis [
3] probably secondary to hyperparathyroidism. On the opposite of case 5, this patient initially had a mild-moderate burden of calcification, but symptoms were quite severe from the beginning. This
late onset form was characterized by progressively worsening cognitive deficits associated with psychotic disturbances partially responsive to therapy. Movement disorders were present from the beginning and continued after suspension and change of treatment. Cognitive impairment was attributable to brain calcifications since it progressed to severe dementia before the appearance of vascular lesions and atrophy.
Finally, case 7 presented a
strio-pallido-dentate calcinosis [
3] probably due to secondary hyperparathyroidism. The patient showed a late onset form with early cognitive and motor dysfunction and later appearance of behavior disturbances. The brain atrophy and the responsiveness of behavioral disturbances to treatment may suggest the disturbances were secondary to degenerative encephalopathy, rather than to BGC. Another possibility is to consider the brain atrophy itself as a consequence of BCG, as neurodegeneration has been reported to occur later in the course of the disease in some cases [
15,
51]. The hypertonia unresponsive to L-dopa could be due to BGC or to cerebrovascular disease, suggested by the anamnestic presence of previous stroke.
The conclusions of our report are limited by the lack of anatomical pathology studies evaluating the real burden of calcification, and by the incomplete information we obtained about some of our cases. However, Fahr’s disease is a quite rare disorder, and by comparing 7 cases (one with each other and with literature) we could suggest some interesting conclusions:
Even with a variable severity, it seems to be a constant finding in patients with basal ganglia calcification; in particular, the two domains most commonly involved in our experience seem to be memory and attention. This observation might result from the fact that basal ganglia play a role in maintaining the integrity of cognitive functions. Alternatively, the calcification of basal ganglia may be a marker of other alterations related to cognitive impairment, such as reduction of cerebral blood flow, atrophy, ischemic sub-cortical lesions. Anyway, our findings strongly argue against the lack of cognitive symptoms in these type of patients.
They are common in patients with basal ganglia calcification, but less than the cognitive decline. In our experience, depression in BGC is resistant to pharmacologic therapy. Anxiety and depression might be secondary to the impairment of the serotonin and dopamine pathways involved in the limbic system. Depression, frequently associated to cognitive impairment, might also represent a phenomenon preceding the onset of dementia, as often happens in the natural history of this disease [
59].
They may be associated to basal ganglia calcification. When present, they are usually severe, with different grade of structure and emotional involvement; nevertheless, we didn’t observe a clear pattern of presentation of psychotic symptoms (different organic background?). Moreover, in agreement with literature, psychosis poorly responds to specific treatment.
We observed only few cases (4/7) of extra pyramidal disorders probably related to the disease; in particular, significant gait disturbances and tremor were developed by the three older individuals. Anyway, a mild extra pyramidal syndrome might have developed also as a side effect of antipsychotic drugs.
In conclusion, while Fahr's disease with early onset seems to present fairly homogeneously, the clinical presentation of late-onset forms of Idiopathic/Secondary BGC seems to be much more heterogeneous, as evidenced by the presented clinical cases and the data from literature.
Based on these results, we discourage the use of the term “Fahr’s syndrome” to describe secondary causes, and prefer referring to them as “Secondary Basal Ganglia Calicification”.
Our data don’t allow to address the border phenotype between physiological calcinosis and putative pathological calcinosis of basal ganglia, since in our case series all of seven cases present some pathological aspects. This result might come from a “selection bias”: working in a Clinic for the study of Cognitive Impairment, most of the patients we evaluate come to our attention because of cognitive/behavioural/mood disturbances. However, we found basal ganglia calcifications in about 0.9 % of our patients, and this result is not different from the 0.8 % found in the general population by Daghighi et al. [
8]. In our case series, basal ganglia calcification never seems to be an isolated and clinically insignificant finding, but always underlies cognitive/psychiatric/motor disturbances. Of consequence, although in some cases basal ganglia calcification might be an occasional finding, some cases (unknown percentage) present with overt clinical symptoms, and the degree of calcification at neuroimaging does not necessary correlate with the severity of clinical picture. Of consequence, we suggest that all subjects with the finding of BGC undergo a screening of cognitive performance and mood state. It could be correct to consider affected by “Fahr’s disease” only people in which BGC have a pivotal role in determining the symptoms, while all conditions in which calcifications are the marginal consequence of different insults to basal ganglia should be labelled as BGC.