Casanova2003 PDF

Psychiatry Research 121 (2003) 5987
Mineralization of the basal ganglia: implications for

neuropsychiatry, pathology and neuroimaging
Manuel F. Casanovaa,b,c,*, Julio M. Araquec
a
Department of Psychiatry, Medical College of Georgia, Augusta, GA 30912, USA

b
Department of Neurology, Medical College of Georgia, Augusta, GA, USA
c
Department of Anatomy, Medical College of Georgia, Augusta, GA, USA
Received 10 October 2002; received in revised form 10 July 2003; accepted 9 August 2003
Abstract
This article examines the evidence for and against the existence of basal ganglia mineralization as a defined
clinicopathological entity. In reviewing the literature on basal ganglia mineralization, this article emphasizes evidence
derived from different neuroimaging modalities, genetics, metabolic studies, postmortem series and their possible
neuropsychiatric correlates. Relevant articles were collected through Medline and Index Medicus searches. Researchers
have encountered multiple difficulties in accepting basal ganglia mineralization as a distinct entity. This syndrome
lacks set clinical criteria or a unique etiology; not surprisingly, numerous articles have applied varied definitions.
Because many of the reported cases have not been examined postmortem, both the extent and nature of their
mineralization remains uncertain. Furthermore, researchers have considered small foci of basal ganglia mineralization
a normal phenomenon of aging. However, when brain deposits are extensive, they are associated with a set of agedependent, progressive clinical symptoms. They include cognitive impairment, extrapyramidal symptoms and
psychosis. Most cases are related to abnormalities of calcium metabolism, but rare familial cases of idiopathic origin
have been reported. Overabundant mineralization of the brain is judged pathological based on its amount, distribution
and accompanying clinical symptoms. Although its relation with calcium dysregulation is well known, modern studies
have emphasized abnormalities of iron and dopamine metabolism. The authors suggest that these metabolic
abnormalities may link basal ganglia mineralization to psychotic symptomatology.
2003 Elsevier Ireland Ltd. All rights reserved.
Keywords: Calcification; Iron; Neuropathology; Schizophrenia; Dementia; Neuroimaging; Computed tomography (CT); Magnetic
resonance imaging (MRI); Positron emission tomography (PET)
*Corresponding author. Downtown VA Medical Center (24), Rm. 3B-121, One Freedom Way, Augusta, VA 30904-6285, USA.
Tel.: q1-706-721-5411; fax: q1-706-721-5409.
E-mail address: casanova@np2.mcg.edu (M.F. Casanova).
0165-1781/03/$ - see front matter 2003 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/S0165-178103.00202-6
60
M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987
1. Introduction
For many years researchers have studied the
function, anatomy and pathology of the basal
ganglia (BG).1 They have linked pathology of
these subcortical masses to both motor abnormalities and psychiatric symptoms. Still, the possible
relevance of mineral deposits within the BG
remains uncertain. Thus far, research has failed to
explain the tendency for certain substances to
accumulate in these specific structures or to provide definite pathophysiological mechanisms for
symptom expression. Similarly, we lack studies on
the cause-effect relationship between early mineral
deposition and later development of symptomatology. Furthermore, one researcher has conjectured
that following lesions of the BG other areas of the
brain may take over some of its functions (Dean,
1989). These considerations hamper attempts at
correlating basal ganglia mineralization (BGM) to
any given set of clinical manifestations.
In most instances BGM is considered physiological and therefore an incidental finding of
either autopsy or clinical investigation. The introduction of neuroimaging techniques requires us to
reappraise this tenet. Modern imaging modalities
provide two distinct advantages capable of addressing gaps in our knowledge regarding BGM. First,
they can screen very large numbers of patients in
a short period of time. Second, they can examine
symptoms in vivo at any stage of a particular
disease process.
The present article summarizes the literature on
BGM with a focus upon neuropsychiatric issues.
We discuss the different methods used in studying
BG deposits. We also correlate the presence of
BGM with clinical and pathological results and
discuss the importance of properly assessing early
deposits. The conclusions from this revision of the
1
Throughout this article we use the term basal ganglia
mineralization (BGM), opening the possibility that other
minerals, beside calcium are involved in this entity. We use
the term basal ganglia calcification (BGC) only when linking
it to a quoted authors description or when referring to X-ray
detection methods that are limited to uncovering calcium
deposits. As a complete analysis of the function and connectivity of BG is beyond the scope of this article, we refer the
interested reader to the review by Ring and Serra-Mestres
(2002).
literature could help institute palliative therapy and

pinpoint a pathological commonality to a variety
of psychiatric conditions.
2. History
Mineralization of the brain has been known for
over a century. Delacour (1850) described ossification of vascular brain structures and referred to
a previously reported case. Virchow (1855) found
spines protruding from the brain sections of a
young man who died of tuberculosis. Bamberger
(1855) independently reported similar postmortem
findings in a man with progressive mental deterioration and seizures. Soon afterwards, other
researchers, including Flesching, Perusini, Greenfield and Durk, described the presence of brain
mineralization in patients with paralysis agitans,
mental retardation, Huntingtons chorea and cerebral syphilis.
Pick (1902, 1903) thought the cerebral calcification in the basal ganglia caused tetany by producing cerebral ischemia. In similar fashion,
Geyelin and Penfield (1929) attributed the condition to an endarteritis with secondary calcification
of the necrotic lesion. Ostertag (1929) recognized
the presence of an albuminoid substance that
served as a nidus for calcification. The albuminoid
material was thought to propitiate calcification
when its mass lesion effect interfered with tissue
circulation and nutrition. Veering from ischemia
and into endocrinopathies, Scheinker (1940) first
postulated a disturbance in albumin metabolism
caused by parathyroid insufficiency. This condition, he believed, led to the formation of toxic
amines that alkalinized the blood, thus propitiating
calcium precipitation.
Geyelin and Penfield (1929) first described
familial mineralization of cortical brain structures
in a father and four of his children, one of whom
had undergone an occipital lobotomy. They found
that mineralization predominantly affected the vessels of the deep cortical layers and adjacent white
matter. In the following year, Fahr (1930) published the case of a 55-year-old man as an example
of idiopathic calcification of the brain vessels.
The patient complained of diarrhea, double vision,
dizziness, and weakness and stiffness of the legs.
61
Table 1
Commonly used terms for non-arteriosclerotic vascular mineralization of the basal ganglia
For the minerals
For the disorder
Calcinosis
Calcification
Calcified bodies
Mulberry bodies
Calcified globules
Bochnicks neurogel
Pseudocalcareous foci
Hirnsteine (stone-hard)
Spatzs pseudocalcium
Senescent calcifications
Physiological calcifications
Morbus Fahr
Fahrs disease
Ferrocalcinosis
Cerebral calcinosis
Striopallidodentate calcinosis
Calcinosis nucleorum cerebri
Symmetrical basal ganglia sclerosis
Idiopathic basal ganglia calcification
Bilateral striopallidodentate calcinosis
Familial striopallidodentate calcification
Corticostriopallidodentate calcifications
Familial idiopathic basal ganglia calcification
Idiopathic familial cerebrovascular ferrocalcinosis
Notes: Lack of agreement as to the proper designation for the non-arteriosclerotic vascular mineralization of the basal ganglia has
given rise to the usage of multiple terms for this entity. It is clear that from all of the terms, those using the eponym of Fahr and
those making reference to calcinosis or sclerosis should be avoided. Fahr was not the first person to describe a case of familial
basal ganglia mineralization. Furthermore, his patient probably had a disorder of calciumyphosphorous metabolism. The term calcification should be avoided because there are other minerals within the vascular concretions. Sclerosis usually refers to a gliotic
response that plays little or no role in the pathology of familial non-arteriosclerotic vascular mineralization of the basal ganglia.
His jaw was firmly locked and his thorax was

strongly arched. After the patients hospitalization,
Fahr noted tremors, hand cramps and eclampsialike attacks. Microscopic examination revealed
extensive calcareous coating of the medium and
small brain vessels. Deposits were most prominent
in the white matter with only traces in the BG;
because the medical literature has misrepresented
this case report, Fahrs name is now attached to a
pathological entity defined by the familial occurrence of disseminated vascular non-arteriosclerotic
mineralization of the pallidum, striatum, dentate,
cortex and centrum semiovale (Lowenthal, 1986)
(Table 1 and Fig. 1).2
2
The designation Fahrs disease is clearly erroneous for
several reasons. First, in his original article, Fahr mentioned
that a number of previous authors had reported similar cases.
In effect, the introduction to his article quotes a number of
precedents. Second, the terminology of Fahrs disease or
Fahrs syndrome fails to describe either idiopathic basal
ganglia calcification, specific causes of calcium deposition in
BG or familial forms of the condition. Lastly, the neurological
symptoms in Fahrs case report are atypical for basal ganglia
mineralization. Rather, they strongly suggest a disturbance of
calcium metabolism, possibly exacerbated by the patients
diarrhea. Therefore, the terminology should be modified, specifying which areas of the brain appear to be most heavily
mineralized, and whether the involved case(s) are familial or
sporadic (Klein and Vieregge, 1998).
Shortly after Fahrs case report, Fritzche (1935)

used skull X-rays to describe the first instance of
extensive mineralization of the BG. An autopsy
report on one of the patients confirmed the presence of mineral deposits in the lenticular nucleus
as well as thalamus and dentate. In the ensuing
years, more than a dozen similar case reports
(Table 2) appeared in the literature, fulfilling most
of the criteria delineated by Moskowitz et al.
(1971) for familial BGC (Table 3).
Although well known for over a century, the
nosological status of BGM remains uncertain. A
major stumbling block to discussing BGM is the
lack of an agreed upon label. Any designation will
have to contest with the wide range of conditions
in which BGM has been reported. In considering
the different appellations, those using the name of
Fahr as an eponym appear to be the most
misguided.
3. Pathology
At the microscopic level, BG concretions are
recognized as basophilic globules tracking the
vessel walls of arteries, arterioles, capillaries and
veins (Fig. 1). Scanning electron microscopy has
shown a connection between some of these bodies
62
Fig. 1. (a) Photomicrograph of the globus pallidus of a patient with familial basal ganglia mineralization and no abnormalities of
calcium metabolism. When extensive, the mineral deposits aggregate to form brain stones (see Fig. 2). In areas less impacted by
minerals, the rectilinear deposits suggest a vascular origin. (b) The intima of the vessels is often spared, but may proliferate to
narrow the lumen.
Table 2
Familial non-arteriosclerotic calcification of basal ganglia vessels
Number of Number of
cases with
cases with
calcification symptoms
Pattern of Impaired
inheritance mental
status
Speech Seizures Pyramidal ExtraCerebellar Cerebellar

Schizophrenia Comments
disorder
signs
pyramidal signs
calcification
signs
Aiello et al. (1981)

Babbitt et al. (1969)
Boller et al. (1977)
Brodaty et al. (2002)
Bruyn et al. (1964)
Caraceni et al. (1974)
Chabot et al. (2001)
Flint and Goldstein (1992)
Ellie et al. (1989)
Foley (1951)
Francis (1979)
3
3
9y9
10
2
2
5
2
2
3y3
8
1
2
3
2
D
?
D
D
Yes
2
3
1
1
1
7
R
D
Fritzche (1935)
Geschwind et al. (1999)
3
12y30
3
11y12
Geyelin and Penfield (1929)

Harati et al. (1984)
Kobari et al. (1997)
Konig
(1989)
sv987?
Kousseff (1980)
Manyan et al. (1992)
Mehta et al. (1986)
Melchior et al. (1960)
5
2
5y6
7
2
6
2
5
2
1
6
2
3
2
5
Moskowitz et al. (1971)

Nichols et al. (1961)
Nyland and Skre (1977)
5
9y13
5
2
7y9
5
Ogata et al. (1987)

Palubinskay and Davies (1959)
Pillery (1966) and Schafroth (1958)
Puvanendran et al. (1982)
Ravindran (1979)
Sala and Savoldi (1959)
Schafroth (1958)
Smits et al. (1983)
Strobos et al. (1957)
3
2
5y5
2y2
3
2
5
2y3
2
2
1
4y5
No
2
2
4
1y3
Totals
143
88
D
D
X-linked
Yes
Yes
Yes
Yes
Yes
Yes
NyA
Yes
Yes
Yes
2y8
Yes
No
D
D
Yes
Yes
Yes
Yes (5)
R
D
R
Yes
Yes
No
Yes
No
No
"
Yes
No
No
NyA
No
Yes
Yes
NyA
No
Yes
No
8y8
Yes
Yes
No
NyA
No
Yes
No
Yes
NyA
Yes
No
Yes
Yes
NyA
No
Yes
Yes
1y3
No
5y8
No
10y10
Yes
Yes
Yes
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
D
D
R(?)
Yes
No
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
D
D
NyA
D
R
Yes
Yes
No
Yes
Yes
4
Yes
Yes
Yes
No
Yes
Yes
D)R
No
No
Yes
Yes
Yes
Yes
1y3
3y9
Yes
qqqq qqq
Yes
No
No
No
No
Yes
Yes
No
qq
No
Equivocal plantar reflexes

CSF pleocytosis, SXR
SXR
SXR
SXR
Dystonia musculorum deformans
3 subjects with schizophrenia
Provides little clinical detail, SXRs

Unusual sensitivity to
neuroleptics, SXR
SXR
Linkage to 14q, classification
based on radiological and
neurological findings
Parietoloccipital mineralization
Glaucoma, microcephaly, loss of vision
Yes
No
Yes
Yes
Yes
qq
Microcephaly, CSF pleocytosis

Microcephaly, demyelination,
pigmentary degeneration
2y5
No
5y5
Yes
No
Yes
Short stature, SXR

Short stature
Provides little clinical detail
Provides little clinical detail, SXR
No
Yes
Yes
No
Yes
qq
No
No
3y5
3y3
No
No
Cerebral palsy, consanguinity

SXR
SXRs, pigmentary macular
degeneration
qs indicate prevalence of
symptoms scale
63
Notes: Rosenberg et al. (1991) reported the case of a patient with schizophrenia and an unusual proclivity for neuroleptic malignant syndrome. The patients endocrinologic evaluation was normal. The patient had a
twin sister and a brother, both of whom had been diagnosed as schizophrenics. CT scan of affected members revealed calcification of the basal ganglia. The clinical presentation of the cases reported by Bruyn et al. (1964)
`
and Strobos et al. (1957) may portray a different disease. The CSF pleocytosis of the patients reported by Babbitt et al. (1969), Mehta et al. (1986) and Aicardi and Gutieres
(1984) suggest an inflammatory rather than
a genetic etiology. Cases of Fritzche (1935), Matthews (1957), Roberts (1959), Beyme (1946) and Nichols et al. (1961) should be classified as Albrights hereditary osteodystrophy. Puvanendran et al. (1982) mentioned
two sisters in his series of basal ganglia mineralization, but gave no further details. The family history of the patient reported by Pillery (1966) stemmed from a previous report by Schafroth (1958). The two brothers
described by Bowman (1954) probably had nephritic syndromes. Neuman (1963) described three brothers admitted to St. Elizabeths Hospital. Two of the brothers had a diagnosis of schizophrenia and autopsy examination
revealed basal ganglia mineralization in both of them. The third brother had suffered from poorly controlled seizures since childhood, but X-rays failed to show any mineralization. The case reports of Weterle and
Rybakowski (1988) and Masuda et al. (1988) could not be translated.
SXRsCalcification established by skull radiography.
Author
64
Table 3
Moskowitzs criteria for familial calcification of the basal ganglia
Bilateral calcification of the basal ganglia
Progressive neurological dysfunction (neuropsychiatric symptoms andyor movement disorder)
Absence of clinical features suggestive of pseudohypoparathyroidism or pseudopseudohypoparathyroidism
Absense of biochemical abnormalities (normal serum calcium and phosphorus, renal tubular responsiveness to parathyroid
hormone)
Evidence for inherited transmission (positive family history)
Absence of an infectious, toxic, traumatic or metabolic origin
Note: The diagnosis can be established in the absence of calcifications or in the absence of neurological dysfunction but not both
if the remaining criteria are fulfilled.
and surrounding glial cells (Kobayashi et al.,

1987). The intima of involved vessels is usually
preserved but occasionally proliferates to narrow
the lumen. In severe cases minerals encase the
whole vessel wall and similar deposits are found
free in the neuropil. Researchers seldom see cell
loss, gliosis and tissue rarefaction. The microscopic
findings differ from those of atherosclerosis where
deposits start in the intima (atheroma) of the larger
arteries.
Histochemical analysis of BG concretions has
revealed the presence of many elements (e.g. iron,
calcium, zinc, copper, magnesium, aluminum,
potassium) within an organic matrix (Adachi et
al., 1968; Duckett et al., 1977; Hurst, 1926; Smeyers-Verbeke et al., 1975). Mucopolisaccharides
deposition (i.e. a nidus of colloidal matrix) precedes that of minerals in basal ganglia, dentate
nucleus, caudate, and gray and white matter areas
of brain and cerebellum (Bhimani et al., 1985;
Petegnief et al., 1999). This matrix is followed by
a deposition of iron and then of calcium (Slager
and Wagner, 1956; Strassmann, 1949; Wagner et
al., 1955). In pathological cases Hurst (1926)
found basophilic deposits (called calcareous) in
50 of 100 autopsies. Excessive accumulation of
minerals follows the pattern of the normal distribution of brain iron.
Ostertag (1929) found deposits in 72 of 100
autopsies. Initially, these deposits were believed to
be calcium. However, research soon identified this
substance as a colloidal albuminoid ground substance (Slager and Wagner, 1956). Strassmann
(1949) found calcium in only 11 of his 280
autopsies and iron in an undetermined number of
cases. When he found increased deposits of iron,
he discovered them also in glia and neurons, where

calcium and iron were always associated. Strassman did not mention the specific site for calcification in his 11 cases. Moreover, he did not focus
his search on the BG. Pathologically, vascular
basophilic deposits predominate in basal ganglia
and dentate nucleus, followed by cerebral and
cerebellar cortex, and caudate (Slager and Wagner,
1956).
Using the ammonium sulfide technique, Spatz
(1922a,b) mapped the normal distribution of brain
iron. He found the greatest concentrations in the
anterior half of the globus pallidus and substantia
nigra. He discovered iron, to a lesser extent, in the
red nucleus, striatum and dentate nucleus of the
cerebellum. Spatz concluded that iron accumulated
in excessive amounts in those brain areas where
metabolic processes required its presence. The
regional distribution of iron is consistent across
species, making generalizations derived from
experimental animals applicable to the human
brain (Sachdev, 1993).
In a postmortem quantification of non-heme iron
levels of 81 adult patients and seven teen brains,
Hallgren and Sourander (1958) demonstrated that
the age-related increases in iron levels reach a
plateau in adulthood. Values of iron concentration
in globus pallidus increase during the first two
decades with no further increase after 30 years of
age. In putamen and caudate, the iron content
increases somewhat more slowly, with maximum
values reached before 5060 years. These authors
determined a maximal amount of iron in the globus
pallidus, followed by red nucleus, substantia nigra,
putamen, and caudate. The highest concentration
in cerebral cortex was found in motor cortex
followed by occipital, sensory and parietal cortex.

No microscopically visible iron was found in the
white matter. The authors suggested that the
increasing iron levels during maturation and aging
reflected an alteration in the enzyme systems of
the cell.
In a histopathological series using the Van Kossa
method for calcium detection, Wegiel et al. (2002)
reported calcification in the globus pallidus and
caudate in 60% and 36%, respectively, of control
subjects (age range 3383). In a sample of 34
patients with Alzheimers disease from 65 to 89
years old, they found 22 with calcification in
globus pallidus (65%), 26% in putamen and 15%
in caudate. Finally, in 23 cases of Down syndrome,
they described calcification in the globus pallidus
of all 23 subjects (100%) with 87% in putamen
and 70% in caudate. Patients with Alzheimers
have a higher incidence of associated mineralization of hippocampal vessels and less BG vascular
mineralization than cases of Down syndrome. The
findings suggest a difference in topography and
pathophysiology underlying mineral deposition in
these entities.
Wagner et al. (1955) reported a series of 200
autopsies from a group of hospitalized patients
older than 15 years. They analyzed the sample
with coronal cuts of 0.75 cm in thickness. Their
radiographic evaluation of the slices correlated
four cases of radiopaque material with histochemical deposits of calcium (ns4y200 or 2%). Using
histological sampling from BG, especially the globus pallidus, they found iron deposit in 68% of
the cases. The authors found that iron accumulation always preceded calcium deposition. Wagners
series is useful as a reference source, because it
uses a radiographic approach to detect calcium and
focuses on BG. However, it is based on autopsies
of patients from several general hospitals with
complicated associated diseases and only includes
patients older than 15 years. Therefore, it probably
reflects a higher incidence of calcification than
found in the general population.
Fujita et al. (2003) examined calcification of
BG and cerebellum using immunohistochemical
methods to demonstrate non-collagenous bone
matrix proteins in 19 brains diagnosed as follows:
five with diffuse neurofibrillary tangles with cal-
65
cification (DNTC), five with Alzheimers disease,

one with Picks disease, one with Parkinsons
disease, one with progressive supranuclear palsy
and six controls. Three patterns of calcium 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), and rows
of small calcospherites lying along capillaries
(type 3 deposition). All cases showed a type 1
pattern of deposition with osteopontin diffusely
present, suggest that this glycoprotein plays an
important role in intracranial calcification in its
early to late states. Type 2 deposition was found
in 14 cases (controls 3y6) and type 3 in 9 (controls
2y6). Osteocalcine was present in the periphery of
calcified regions, suggesting a role in the later
stages of intracranial calcification. Bone sialoprotein and osteonectin were found only in core
portions of type 2 and 3 depositions. Different
calcium deposition patterns of non-collagenous
bone matrix proteins suggest their separate roles
in the pathogenesis of intracranial calcification.
Since type 3 deposition was found in all cases of
DNTC, this pattern is considered a hallmark of
severe intracranial calcification.
Research suggests that the rate of accumulation
for mineralization of the BG varies according to
the underlying etiology. In cases of postoperative
hypoparathyroidism, albuminoid deposits appear
in approximately 9 years, contain iron after 12
years and become calcified in approximately 24
years (Slager and Wagner, 1956). Iwasaki et al.
(1988) described the development of BG calcification 9 days after an initial CT scan in a 58-yearold woman with insulin-dependent diabetes
mellitus, as well as a postoperative hypoxemia and
metabolic acidosis that caused her death. Sarwar
and Ford (1981) examined a case involving anoxia, alcoholism and pancreatitis. Thirty one days
after a CT scan they found no calcification in the
BG, a second CT scan detected calcification.
Midroni and Willinsky (1992) described a 22year-old man who presented bilateral BGC within
17 days of an anoxic insult.
In the early stages of BGM, basophilic globules
delineate an organic matrix tracking the abluminal
portion of the smaller vessels. The orderly pro-
66
gression of mineral deposition within this matrix

counters the mechanistic explanation of a passive
sieve-like effect. The topography of brain mineralization suggests that the organic matrix provides
a nidus for the normal accumulation of iron. Some
pathological states accentuate iron deposition within the BG we.g. Friedreichs ataxia, progressive
supranuclear palsy, Huntingtons, Parkinsons and
HallervordenSpatz diseases (Berg et al., 2001b;
Yantiri and Andersen, 1999)x. Other specific minerals may be of importance in parathyroid-related
disorders (i.e. calcium) and in Wilsons disease3
wi.e. copper (Faa et al., 2001)x. When the hippocampus is affected, Alzheimers disease should be
suspected.
4. Pathophysiology
Historically, the mechanism(s) accounting for
the accumulation of minerals, iron in particular,
have been contested in the literature. Klotz (cited
by Hurst, 1926) believed that accumulations resulted from an interaction between fatty acids and
calcium. Other investigators proposed either an
affinity towards necrotic material or colloid precipitation. Scattered reports have also postulated
dysoric (i.e. rupture of the blood-brain barrier),
toxic, inflammatory, genetic or vasculitic origin for
these accumulations (Lowenthal, 1986; Lowenthal
and Bruyn, 1968; Morgante et al., 1986). Since
extensive mineralization follows a watershed distribution, a vascular or dysoric etiology seems
most likely (Norman and Urich, 1960; Lindenberg
and Haymaker, 1982).
The BG have a high metabolic rate, a peculiar
vascular supply, and autoregulation facilitating
increased vascular permeability. Progressive BGM
can compress the vessel lumen, thus initiating a
vicious cycle of impaired blood flow, neural tissue
injury and mineral deposition (Bhimani et al.,
1985; Sarwar and Ford, 1981). In neonatal ischemia, Rodriguez et al. (2001) mention neuronal
damage associated with astroglial and microglial
reaction and calcium precipitates in BG; these
3
Although mineral deposits in the BG are occasionally
encountered in Wilsons disease, both the pattern and extent
of these deposits differ from that found in familial BGM
(Harik and Post, 1981).
authors believe excitatory amino acid receptors

participate in the damage. Lack of oxygen leads
to depolarization of membranes, release of the
neurotransmitter glutamate and excitotoxic cell
death (necrosis). Compounding a possible ischemic genesis, some authors believe that the accumulation of iron could impair antioxidant defense
mechanisms (Warren et al., 2001).
Iron may play a critical role in the pathogenesis
of neuronal degeneration. Iron catalyzes reactions
forming oxygen radicals, which can induce damage
to the mitochondrial electron transport, induction
of proteases and increased membrane lipid peroxidation. Therefore, increased iron levels in BG
may induce iron-stimulated oxidative damage in
these tissues and accelerate neuronal degeneration.
Finally, these reactions may result in death of the
cell or induce a system less able to defend itself
against noxious stimulus (Berg et al., 2001a; Double et al., 2002). Oxidative stress affects both glial
cells and neurons, causing a general metabolic
failure. Oxidative stress is intimately linked to
other components of the degenerative process and
cellular death, such as mitochondrial dysfunction,
excitotoxity, nitric acid toxicity and inflammation.
It is difficult to determine whether oxidative stress
leads to or is a consequence of these events.
Probably, as has been suggested in Parkinsons
disease, oxidative stress can be both an initiator
and a component of cell degeneration (Jener,
2003). Mitochondria regulate cell death and survival through their role in energy production and
calcium homeostasis. Due to a high metabolic rate,
oxygen radicals are generated in the mitochondria.
These structures probably play a role as initiator
and target of oxidative stress (Blomgren et al.,
2003).
Elevated intra-cellular calcium levels also have
been implicated in the pathogenesis of neurodegenerative brain disorders. The intracellular overload of calcium levels causes conversion of
xanthine dehydrogenase to xanthine oxidase,
which produces superoxide anion and cell injury
(Obata, 2003). Calcium may also participate in
excitotoxic death by activating proteases and
destroying the cytoskeleton (Levitan and Kaczmarek, 2002).
5. Animal models of basal ganglia mineralization

Researchers have occasionally found mineralization of the BG in animals. Gavier-Wider et al.
(2001) described mineralization of blood vessel
walls in the internal capsule of asymptomatic 7year-old cattle. They found inflammatory vascular
infiltrates in 30% of the animals (ns506 brains)
and associated vascular mineralization with aging.
In a group of 20 healthy 3- to 10-year-old horses,
Yanai et al. (1996) found cerebral mineralization
in pallidal arteries of 12 (60%) horses. They also
described amorphous deposits in the walls of
arterioles, small- or medium-sized arteries and
veins. In addition, small globoid bodies tested
positive for periodic acid Schiff (PAS) reaction
adjoining capillaries. Interestingly, these deposits
also revealed the presence of aluminum, phosphorous, zinc, calcium, iron and small amounts of
sodium. Yanai et al. (1994) similarly described
the histological appearance of deposits in 79 out
of 134 monkeys.
Stereotactic injection of excitatory amino acid
analogues such as e.g. ibotenic acid (IBO) in the
rat ventral globus pallidus, induced formation of
round calcium deposits and partial disappearance
of nerve cells (Mahi et al. 1995, 1999). In addition,
Mahis group identified the accumulation of calcium and inorganic phosphorous by apoptotic cells
as the primary mechanism of mineralization. Interestingly, the precipitants that occur in the cytoplasm and is made up of inorganic components:
calcium and phosphorous, accompanied by sulfur,
aluminum, silicon and potassium. By injecting rats
with either alpha-amino (3-hydroxy-5-methyl-4isoxazol-4-il)-propionic acid (Bernal et al., 2000)
or N-methyl aspartic acid (NMDA) (Stewart et
al., 1995), calcification is produced at the site of
injection. Stewart et al. (1995) found destruction
of basal forebrain cholinergic neurons 11 months
after injecting NMDA in nucleus basalis of adult
rats.
Besides IBO and NMDA, researchers have used
excitotoxins like kainic acid and alpha-amino-3hydroxy-5-methylsoxazole-4-propionilic
acid
(AMPA) to produce mineral deposits. Such deposits have been noted well outside the boundary of
67
cell loss, making it unlikely that this condition is

a direct response to injury caused by the needle
tract. At the injection site, neuronal death is due
to calcium influx. This disturbance in calcium
metabolism might form the basis for mineralization
at this location (Stewart et al., 1995). It is important to note that the presence of gliosis when using
any of the aforementioned excitotoxic agents suggests a different pathology from that observed in
human BGM.
Other experiments in vitro demonstrate that
glutaminergic agonists cause calcium accumulation. Petegnief et al. (1999) activated astrocytes
and microglial cells by administering AMPA. They
then administered NBQX (i.e. a selective AMPA
antagonist), which blocked the calcium deposition.
Their work suggests that calcium deposition causes
microglial activation, but may partially block an
astroglial response. It should be noted that an
astroglial reaction is more directly related to neuronal damage than microglial activation.
Mahi et al. (1999) postulated that (astro)gliosis
is a defense mechanism triggered by attempts to
limit the damage produced by increased amounts
of calcium. Injured cells responding to the chronic
release of glutamate liberate infusions of calcium;
therefore, calcium precipitation would be a compensatory mechanism for excitotoxic degeneration.
An associated microglial reaction could explain
further damage related to cytokine liberation.
Alterations of dietary mineral can provide for
changes in their brain levels. Studies have shown
that low dietary calcium and magnesium, in conjunction with high aluminum content, lead to high
calcium and low magnesium levels in the central
nervous system and spinal cord. These phenomena
have been associated with amyotrophic lateral
sclerosis, Parkinsons dementia, and calcification
of spinal ligaments in patients from the Kii Peninsula of Japan. In effect, Yasui et al. (1991a,b,
1997) have experimentally mimicked the environmental factors in the Kii Peninsula and have found
a similar alteration in levels of magnesium and
calcium in rats and macaques. The result suggests
that an analogous mechanism could mobilize calcium and magnesium from bone for ultimate deposition in human BG.
68
Towfighi et al. (1991) studied the amount of

hypoxia required to produce damage in immature
rats. They found lesions that often showed mineralization after unilateral carotid ligation. The tendency to produce dystrophic calcifications after
ischemic lesions appears principally in immature
neurons in animals and in perinatal cerebral lesions
in human infants. The condition probably results
from a sublethal injury to the neuron and an
immature inflammatory reaction lacking in lytic
enzymes.
Experiments with animal models offer interesting parallels with some human conditions. The
evidence presented by these studies suggests a role
for excitotoxins in animal BGM and its possible
extrapolation to humans. However, none of the
experiments involving excitotoxic lesions mentions
vascular deposits. This is a serious shortcoming,
as small vessel accretions are a prominent finding
in human BGM.
6. Radiology
Neuroimaging studies have been useful in the
antemortem diagnosis of BGM. Although the medical literature has not defined the exact incidence
of BGM in skull X-rays (SXR), it has considered
it minimal. Muenter and Whisnant (1968)
reviewed the experience of the Mayo Clinic from
1935 to 1966 and found only 38 cases. Approximately 25% of patients with BGM in SXR manifested some type of movement disorder (Muenter
and Whisnant, 1968; Lowenthal and Bruyn, 1968).
Almost 70% of them had abnormalities of calcium
metabolism (Bennett et al., 1959). Examining a
series using CT, Illum and Dupont (1985) detected
BGM in 69% (ns11y16) of patients with idiopathic hypoparathyroidism and 100% (ns8y8) of
those with pseudohypoparathyroidism. Other metabolic conditions do not share the same high
incidence of BGM. Kendall and Cavanagh (1986)
reported only six cases of intracranial calcification
in metabolic disorders after having evaluated
18,000 CTs.
In comparison to SXRs, CT scanning is capable
of increased detection of BGM (Rossi et al., 1993)
(Table 4 and Fig. 2). According to phantom studies
by Norman et al. (1978), CT detects intracranial
mineralization with 515 times the sensitivity of

SXR. More recent studies argue for still larger
differences in sensitivity. Fenelon

et al. (1993),
using SXR, found calcification in only one out 24
cases of calcification detected by CT. Similarly,
the Kazis series (1985) observed BGM in 1.02%
of 7040 CT scans, yet SXRs detected only 4.2%
of the cases showing mineralization on CT scan.
Most cases identified by CT scans are asymptomatic (Vles et al., 1981).
The discrepant sensitivity between neuroimaging modalities and the putative relevance of their
reported findings has created confusion regarding
the existence of a clinical syndrome related to
BGM. This negative ideation has been compounded by: (a) the inclusion within the same series of
completely different types of mineralization (Lowenthal, 1986); and (b) the low prevalence of
familial BGM cases in the general population.
Researchers have nevertheless supported the existence of symptomatic BGM and distinguish it from
the physiological or senescent mineralization of
the BG based on the relative amount of iron and
calcium (Bruyn et al., 1964; Hurst, 1926; Lowenthal, 1986), and in the absolute content of otherwise rare trace metals such as zinc, aluminum and
magnesium (Duckett et al., 1977).
Some authors have argued that the severity of
mental disorders may correlate better with cortical
atrophy than with the amount of BGM (Kazis,
1985). Numerous neuroimaging studies have disputed this claim. Chabot et al. (2001), for example,
believe that the risk of developing schizophrenia
could be proportional to the extent of calcification.
Kowdley et al. (1999) correlated the extent of
calcification with a higher degree of cognitive
impairment. Avrahami et al. (1994) correlated size
of calcification with severity of the disease. These
investigators linked the volume of calcification to
the presence or absence of neurological symptoms,
but they found no correlation between intracranial
calcification and neurological symptoms. However,
their research included only patients whose calcification extended more than 800 mm2. Then, too,
the average age in the control group was 44 years
old, while the average age in the group with
neurological disease was 58.
Table 4
Computed tomographic series on basal ganglia calcification
Frequency of
basal ganglia
calcification
Number
of cases
examined
Age range of cases

with basal ganglia
calcification
Abnormalities
of calcium
metabolism
Seizures
Dementia
Psychiatric
symptoms
Extra-pyramidal
symptoms
Koller et al. (1979)

Murphy (1979)
Sachs et al. (1979)
Brannan et al. (1980)
Cohen et al. (1980)
Danzinger et al. (1980)*
Harrington et al. (1981)
0.33%
0.75%
0.40%
0.36%
0.60%
0.59%
0.60%
(42y7000)
4y262 (1.5%)
1.5%
1.02%
0.60%
1.1%
1.1%
2.5%
1.0%
143y14 206
30y1478
2.03%
42y4500
4219
7081
3800
12 000
5000
17
7000
3189
584
2079
1086
3070q
NA
NA
0y14
0y46
NA
3y26
2y32
17y17
1y26
0y14
0y53
9y14
3y38
NA
NA
8y26
1y14
NA
NA
10y38
NA
NA
NA
NA
NA
12y14
NA
NA
NA
NA
1y14
3y53
3y14
1y38
NA
NA
NA
262
3164
7040
5987
4283
6348
725
14 206
1899 (mean 42.7)

885
2668
050q
0.520
NA
2387
1686
No
0y47
14y72
0y37
1y19
NA
0y18
0y143
1y4
11y47
15%
28y37**
18y48
6y35
6y18
4%
2y4
4y47
NA
NA
NA
4y62
8y18
37%
4y4
1y47
NA
NA
NA
25y70
7y18
27%
1y4
1y47
15y72
NA
0y18
21y35
4y18
NA
1478
3190
8y30
1y30
NyA
NyA
NyA
4500
984 (mean 43)
3y42
22y42
3y42
4y42
Haskins and Leslie (1992)

Puvanendran et al. (1982)
Kazis (1985)
Ogata et al. (1987)
Legido et al. (1988)
Konig
(1989)
Casanova et al. (1990a)
Forstl
et al. (1991)
Fenelon
et al. (1993)
Sanchetee et al. (1999)
*
Author
All of the patients examined in this series had abnormalities of calcium metabolism.
The population examined consisted of 5196 epileptics and 791 non-epileptic patients.
**
69
70
Fig. 2. A brain CT scan reveals large accumulation of minerals (brain stones) in the basal ganglia of a schizophrenic patient. Two
other members of the patients family, the brother and mother, also had equally prominent mineralization of the brain. The brother
had a diagnosis of schizophrenia, and the mother was a recluse who stored garbage in the refrigerator and argued with the television
set. Laboratory tests showed no abnormalities of calcium metabolism in any of the family members.
In a group of patients with BGC, Forstl

et al.
(1991) found a high frequency of affective and
psychiatric disorder. At the same time, they
acknowledged a possible selection bias, because
both the control group and the BGC calcification
group came from a psychiatric institution. A subsequent study by the same group analyzed 166
patients with BGC in their CTs (Forstl

et al.,
1992). The mean age of their BGC patients was
67 years as compared to 50 years for their control
group (ns622 patients). They found a weak statistical association between neurological disturbances (i.e. alcohol dependence, head trauma,
headache, vertigo, epilepsy, dementia, brain
infarct) and calcification that was not increased
after making an odds ratio evaluation. These studies suffer from several limitations. It is known that
the older the patient with mineral deposits, the
greater the possibility of longstanding disease and
neurological symptoms. Accurately quantifying the
elements related to calcium deposits requires comparisons between groups of equivalent age. In such
studies, neuroimaging techniques should also try
to quantify the amount of minerals deposited at a
particular stage (early or late) within the natural
history of the condition of interest.
It is worth noting that in families exhibiting
widespread mineralization of the brain, approximately half of the younger cases are asymptomatic
(Ellie et al., 1989). In contrast, of the 42 cases
reviewed by these authors, all patients over 45

years of age manifested some clinical symptoms
attributable to mineralization. The progressive
nature of the disorder clearly differentiates it from
the benign forms found incidentally by either CT
scans or in postmortem series. CT studies are not
screening exams; they are applied to people with
a particular symptomatology such as headache,
dizziness, or trauma. Furthermore, the exam is
applied to patients whose complaints range from
mild to more serious, and the results cannot distinguish calcium from other mineral deposits.
Notwithstanding the selection bias of CT, this
neuroimaging modality is the preferred method to
localize and assess the extent of cerebral calcifications. Future attempts at prospective screening
and quantification should consider a simple method like that originated by Philpot and Lewis
(1989). The modification suggested in Kowdley
et al. (1999) uses a 03 rating scale: 0sabsent;
1sfaint (punctuate but definitive densities); 2s
definitive (dense but limited calcifications); and
3sdense (multiple calcifications). Using this rating scale to describe BGCyBGM should yield
relevant comparisons when conducting follow-ups
on selected patients.
Transcranial ultrasound is an applicable technique used for in vivo quantification of iron in the
substantia nigra and BG. There is a close correlation between echogenicity of substantia nigra and
tissue iron content (Becker and Berg, 2001; Berg
et al., 2001a). This technique has been used to
characterize and follow up iron deposits in Parkinsons disease, thus providing a method for studying
nigrostriatal function.
MRI is more versatile than transcranial ultrasound in being able to quantify in vivo different
indicators of tissue damage: iron, minerals and
amount of water. Scotti et al. (1985) found different MRI signals from mineral deposits in the basal
ganglia, white matter and cerebellum of a single
patient with Fahrs disease. They attributed this
signal variability to the presence of different
amounts of mucopolysaccharides deposits. The
low proton density of calcium usually exhibits
areas with low signal in T1 and T2 images, making
it difficult to detect calcium in MR images. It is
now known that calcium itself could cause the
71
rare appearance of hyperintense signal in T1 images of MRI. This hyperintense T1 signal in calcified
areas may be explained by the shortening of the
T1 relaxation time of hydrogen protons next to the
surface of the calcium crystals. Concomitant to
hyperintense T1 images, areas of calfications also
reveal a shortening in the T2 signal (Avrahami et
al., 1994; Boyko et al., 1992; Dell et al., 1988;
Henkelman et al., 1991). The findings of diverse
signals from calcified areas may reflect a difference in stages of the disease and parts of the brain
parenchyma affected. However, diversity in signal
intensity could also be due to both the mineral
content and its surface characteristics.
Radiation therapy and chemotherapy have also
related hyperintensities in T1 images to mineralization microangiopathy (Shanley, 1995). Henkelman et al. (1991) have suggested that a
paramagnetic moiety or iron could alter the MRI
signal intensity. MRI using T2* and GradientRecalled Echo (GRE) images is useful to detect
small areas of hemorrhage or calcifications that
appear as hypointense foci. They may be differentiated using corrected gradient echo phase imaging: chronic hemorrhages that are paramagnetic in
nature appear dark (negative phase), whereas the
diamagnetic calcifications appear white (positive
phase) (Gupta et al., 2001). In BG calcification,
the concomitant iron accumulation involves a negative phase (dark appearance) (Yamada et al.,
1996).
CT scanning is immensely more sensitive than
SXR in detecting brain calcifications. Although
considered the method of choice for both prospectively screening and assessing the extent of BGM,
its research value has been limited by its inability
to resolve the elemental constitution of mineral
deposits. Thus, the ability of MRI to quantify
physiologic forms of iron may be of relevance in
evaluating those neurodegenerative disorders at
risk of damage by free radical neurotoxic processes
(Bartzokis et al., 1994). A practical example of
this potential application has been provided by
Righini et al. (2002), who used 3-mm-thick slices
to correlate increased iron accumulation in the
putamen with a T2 hypointensity when distinguishing striatonigral degeneration and Parkinsons disease. In this same study neuronal loss and gliosis
72
correlated with hyperintensities in T2 and proton

density images.
7. Functional neuroimaging
Functional methods of neuroimaging include
positron emission tomography (PET), single photon emission compute tomography (SPECT), magnetic resonance spectroscopy (MRS), functional
magnetic resonance imaging (fMRI) and xenon
compute tomography (Xe-CT). All have a long
history of use to study neural physiology and
psychiatric alterations (Grady and Keightley,
2002).
Various techniques for measuring regional cerebral blood flow permit the study of many psychiatric conditions. Initially, the xenon-133 inhalation
technique was used, followed by the widespread
use of SPECT. All of these studies must take into
consideration the pharmacological treatment of the
patient as a variable. Cerebral blood flow images
(CBF) using Xe-CT show a resolution high
enough to demonstrate a lower flow to the globus
pallidus than to the putamen, probably due to the
reduced cellularity in globus pallidus (Haku et al.,
2000). Flow to BG can be also estimated using
transcranial Doppler ultrasound (Brauer et al.,
1998).
Using SPECT makes it possible to evaluate the
blood flow to the basal ganglia. Fujii et al. (1995)
used N-isopropyl-w123Ix p-iodoamphetamine (IMP)
to measure blood flow in mitochondrial encephalopathies. They found bilateral normal BG perfusion in a case of MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) with CT-determined BGC. They found a
link between ischemia and lactic acidosis but not
4
Not every case of pseudohypoparathyroidism has detectable mineralization on computed tomography (CT) (Evans and
Donley, 1988). Using CT, Huddle and Ally (1989) found four
cases of BGC in their nine cases of idiopathic hypoparathyroidism. Three of those patients had epilepsy, but none had
extrapyramidal features. Pumarino et al. (1989) described 10
cases of idiopathic hypoparathyroidism, four of which exhibited BGC. Mithal et al. (1989) described 13 patients from 4
months to 20 years of age (mean 9 years) with spontaneous
hypoparathyroidism; they found BGC in five out of nine CT
scans.
with angiopathy. The normal perfusion probably

demonstrates vascular patency in this syndrome.
Global metabolic rate in BG could be evaluated
using positron emission tomography (PET) with
18
F-fluorodeoxyglucose (FDG) (Henry et al.,
et al. (2000) used FDG to study
2001). Molnar
subjects with mitochondrial disorders. They found
only mild changes in glucose metabolism in BG,
thalamus and posterior parietal lobule that did not
suggest the presence of an angiopathy. A neuroimaging study using PET (FDG) with CT in four
subjects detected BGC and metabolism changes in
calcified tissues. Cortical metabolism was normal
even in two subjects with impairment in neuropsychological tests (Staffen et al., 1994).
Only a handful of functional neuroimaging studies have focused their attention on BGM. Noted
changes have been mild and indicative of normal
perfusion within affected BG. However, no single
neuroimaging test is useful in appraising BG function. The best designed studies will require a
combination of different imaging modalities.
8. Clinical syndromes
Eaton et al. (1939) first described the occurrence
of BGM in idiopathic hypoparathyroidism. Several
years later researchers recognized its occurrence in
pseudohypoparathyroidism and Albrights disease
(Alexander et al., 1949; MacGregor and Whitehead, 1954; Sprague et al., 1945). The association
of vascular mineralization of widespread areas of
the brain with disorders of calcium metabolism
andyor a positive family history enabled clinicians
to propose the following nosologic classification
(Billard et al., 1988; Lowenthal, 1986; Lowenthal
and Bruyn, 1968):
The first group consists of cases of hypoparathyroidism,
pseudohypoparathyroidism
and
pseudopseudohypoparathyroidism4. Clinical features include seizures and mental deterioration
(Foley, 1951). Episodes of confusion and psychotic behavior punctuate the clinical course until coma
supervenes. Cranial nerve palsies are unusual
except for nerve deafness. Common early symptoms include paresthesias and muscular disorders
(cramps, pain and stiffness). Kowdley et al. (1999)
found BGC in six out of 10 hypoparathyroid
subjects with a positive correlation between severity of calcification and cognitive deficit. Usually,
symptoms like poor concentration, impaired memory, disorientation and apathy resolve with the
correction of the hypocalcemia (Hossain, 1970;
Illum and Dupont, 1985; Tambyah et al., 1993).
Permanent cognitive and motor deficits associated
with calcifications are probably related to neuronal
loss or an ischemic mechanism. In addition, many
cases of pseudo- and pseudopseudohypoparathyroidism manifest ectodermal changes including
sparse hair, brittle nails, rough and puffy skin, and
malformed teeth.
In the second group, neurologic symptoms are
associated with sporadic cases of BGM. The onset
is usually in adolescence or middle age; the symptoms change with the location of the pseudocalcareous foci. The disease is slowly progressive,
shows predominantly hyperkinesis of different
types with a tendency to develop increased tone,
rarely onset with akinesis. Associated may be
ataxia, dysmetria and cerebellar speech disturbances. If the internal capsule is involved, hemiplegia or paraplegia may occur. Frequently
epileptic or tetanic fits are associated, as well as
progressive mental deterioration wdescribed by
Volland (1940) and translated by Muenter and
Whisnant (1968)x. When symptoms occur in children, they take the form of an encephalopathy
without any clear progression or accompanying
somatic findings (e.g. absent short stature or retinal
abnormalities) (Billard et al., 1988).
The third group consists of familial cases not
related to disturbances of calcium metabolism
(Table 2). The pedigrees of adult familial cases
are most commonly consistent with an autosomal
dominant mode of inheritance. Geschwind et al.
(1999) described a susceptibility locus for this
disease on chromosome 14q in 24 members of the
same family. These authors also described a genetic contribution to the symptomatology: dystonias,
poor performance on frontal system tasks,
migraine, schizophreniform psychosis and Parkinsonism. Symptoms usually start between 30 and
50 years of age (Ellie et al., 1989). Mental
deterioration is progressive and often leads to
dementia. More than 95% of affected patients
develop clear symptoms and findings of minerali-
73
zation on CT scans by the age of 50 years, but

some are clinically symptomatic in the absence of
CT-demonstrated calcification. Symptomatic cases
with no initial evidence of calcification revealed
calcification in follow-up examination. These findings suggest that macroscopic calcifications are
not the primary causal insult.
Extrapyramidal, pyramidal and cerebellar symptoms are common in the third group (Klein et al.,
1997). When present, dysarthria may be related to
bilateral putaminal damage (Lowenthal and Bruyn,
1968). Seizures, not tetanic contractions, are commonly observed (Kuroiwa et al., 1982). Families
with autosomal recessive inheritance (Bruyn et al.,
1964; Caraceni et al., 1974; Kousseff, 1980; Melchior et al., 1960; Nyland and Skre, 1977) have
an earlier onset of symptoms and often share the
clinical manifestations of Cockaynes syndrome
(microcephaly, dwarfism, progeria, retinal degeneration or optic atrophy and mental retardation)
(Bowman, 1954; Laubenthal and Hallervorden,
1940; Menegati et al., 1981; Neill and Dingwall,
1950; Smits et al., 1983; Troost et al., 1984; Xuezhe et al., 1989). In some cases, patches of
demyelination have accompanied mineralization.
MRI demonstrates those patches of demyelinization as hyperintensities in T2 weighted sequences
in BG, thalami, dentate, spinal cord and white
matter (Faerber and Poussaint, 2002).
T2 hyperintensities in BG appear in practically
all cases of mitochondrial diseases. A muscle
biopsy, plus clinical and imaging information, is
recommended to exclude the possibility of a mitochondrial myopathy (Hilton Jones, 1982; Seigel et
al., 1979). Other mitochondrial disorders such as
Pearsons syndrome (Lacbawan et al., 2000) and
maternal inherited diabetes and deafness (Lien et
al., 2001) have been associated with BGM. BGC
is the most common neuroimaging finding in cases
of mitochondrial myopathy encephalopathy, lactacidosis and stroke (MELAS). These patients may
present with seizures, headaches, temporary paralysis (stroke-like episodes), muscle weakness and
ophthalmoplegia. Other clinical manifestations
include depression and dementia. Sue et al. (1998)
found CT calcification in 14 out of their 22 patients
(63%). They suggest that calcium accumulates in
the mitochondria and deposits as salts during stress
74
periods. One postmortem study showed no mineral

deposition within BG or neuronal loss. None of
the patients showed signs of BG dysfunction.
Interestingly, Sue et al. (1998) suggest that BGC
is a marker of MELAS but does not cause symptoms; neuroimaging studies have not associated it
with BG perfusion alterations.
More recently, the introduction of molecular
techniques has enlarged the number of disorders
with familial BGM (third group, vide supra). Thus,
`
Aicardi and Gutieres
(1984) described a progressive encephalopathy characterized by BGM, leukodystrophy, normal head circumference at birth,
chronic cerebrospinal fluid (CSF) lymphocytosis,
and negative serological prenatal infection screening associated with elevation of CSF interferon-a
(IFN-a). The condition is inherited as an autosomal recessive trait. Crow et al. (2000) have
described a linkage to chromosome 3p21 in 21 out
of 23 patients with the condition. Eight patients
had extension of the calcification to the white
matter and five to the dentate nucleus. Of the two
cases without BGM, one was evaluated with MRI
and the other had mineralization exclusive to the
white matter. The BGM is virtually a constant
`
finding in this condition. Goutieres
et al. (1998)
report 27 cases, with BGC present in 26 of them.
These patients also presented brain atrophy and
developed microcephaly during the first year of
life. Some cases exhibit congenital microcephaly.
However, seizures are not a prominent finding,
and typical manifestations tend to disappear with
age (McEntagard et al., 1998). These conditions
should be differentiated from congenital infections
and pseudo-TORCH syndrome. High levels of
IFN-a might be a causal factor for the encephalopathy that develops in transgenic mice receiving
astrocyte target IFN-a. These animals also develop
`
BGC (Goutieres
et al., 1998). Brodaty et al.
(2002) have reported a dominant pattern of inheritance of BGM independent of neurological, cognitive and psychiatric symptoms. They scanned 30
members of the same family, finding 10 cases with
BGM. This group has no association with the
locus described by Geschwind et al. (1999) and
may represent a second locus for this disorder
lacking connection with any of the identified or
probable dementia genes.
Kurup and Kurup (2002) described BGC in six

out of 10 members of the same family affected by
a complex group of disorders such as Parkinsons
disease, syndrome X, rheumatoid arthritis, systemic tumors and schizophrenia. These authors
described an increase in endogenous digoxin that
inhibits the enzyme NaK ATPase, increasing the
intracellular calcium that produces BGC. This
increase in calcium occurs along with a decrease
in intracellular magnesium and seric level of tyrosine as well as an increase in seric level of
tryptophan. A schizoid neurotransmitter pattern
appears: reduced dopamine, noradrenaline and
morphine, with increased serotonin, strychnine and
nicotine.
Disorders expressing vascular BGM have been
divided into three groups. The first one relates to
disorders of the parathyroid gland. Neuropsychiatric symptoms are fluctuating and often reversible
with treatment. Ectodermal findings occur in a
significant proportion of patients. Urinary excretion of phosphorus and cyclic-AMP at baseline
and after administration of exogenous PTH (Ellsworth Howard test) should be requested to evaluate
parathyroid function. Symptoms are slowly progressive in the second group, sporadic BGM. The
third group is composed of familial cases, usually
of autosomal dominant inheritance, not related to
parathyroid abnormalities. Symptoms are progressive and often lead to dementia. Many cases within
this third group emphasize the role of the mitochondria in BGM.
9. Miscellaneous conditions related to basal
ganglia calcification
In a review of the literature, literally hundreds
of isolated descriptions relate diverse diseases and
conditions to BGC. Their methods vary from
radiographic, to histopathologic, to clinical. Usually the lack of unified criteria fails to permit
grouping these cases by conditions, tendencies or
common origin (Table 5). We have, however,
selected a group of these reports that emphasizes
psychiatric alterations or describes possible physiopathological mechanisms. In these cases, it is often
difficult to be sure if BGM has caused or resulted
from the disease or symptomatology. These con-
Table 5
Disorders associated with basal ganglia calcification
Congenitalydevelopment
Inflammatoryyinfectious
Toxicyanoxic
Degenerativeymetabolic
Miscellaneous
Hypoparathyroidism,
Pseudohypoparathyroidism,
Pseudo-pseudohypoparathyroidism,
Addisons disease,
Hyperparathyroidism,
Hypothyroidism
(cretinism),
Kallmans syndrome,
Allbrights disease,
Kenny-Caffey syndrome,
Maternal inherited diabetes
and deafness
Familial idiopathic cases

(Fahrs disease),
Cockayne syndrome,
Tuberous sclerosis,
Oculocranio-somatic
disease,
Amaurotic idiocy,
Mitochondrial
encephalomyopathy,
Hidrotic ectodermal
dysplasia, MorgagniMorel syndrome,
Dyskeratosis cogenita,
Lipomembranous
polycystic osteodysplasia,
Downs syndrome,
Hyperphenylalanimemia
(dihydropteridine
reductase deficiency),
Lipod proteinosis
(hyalinosis cutis),
HastingsJames syndrome
(idiopathic lenticulodentate calcification),
`
Aicardi-Goutieres
syndrome,
Raines syndrome,
Coats syndrome,
Pearsons syndrome.
Cytomegalic inclusion
disease,
Encephalitis (measles,
chicken pox, mumps
etc.),
Toxoplasmosis,
Cysticercosis,
AIDS,
Tuberculosis,
Congenital rubella,
Epstein-Barr virus,
Syphilis,
Brucellosis
Carbon monoxide
intoxication,
Lead intoxication,
Birth anoxia,
Therapeutic radiation,
Methotrexate therapy,
Anticonvulsant
medications,
Strokeyanoxiayhypoxia,
Methanol intoxication,
Cerebral hemorrhage,
Necrotic brain tissue,
Mercury poisoning
Hallervorden-Spatz,
Paramyloidosis,
Myotonic dystrophy,
Parkinsonism,
Huntingtons chorea,
Type 1 gangliosidosis,
Membranous
lipodystrophy,
Wilsons disease,
Picks disease,
Alzheimers disease,
Renal tubular acidosis,
Mitochondrial diseases,
Dentato-rubropallidoluysian atrophy
(DRPLA), Progressive
supranuclear palsy,
Mitochondrial
encephalopathy with
lactic acidosis and
stroke-like episodes
(MELAS), Kearns-Syre
syndrome,
Diffuse neurofibrillary
tangles with calcification.
Systemic lupus
erythematosus,
Scleroderma,
Carbonic
anhidrase II
deficiency,
Osteopetrosis,
Tumors
(germinoma,
ganglioglioma),
Folate
deficiency,
Celiac disease,
Normal aging.
Endocrine
75
76
ditions include unusual associations like neurocysticercosis

(Delgado-Rodriguez,
1984),
toxoplasmosis (Al Shahwan et al., 1996), myotonic dystrophy (Avrahami et al., 1987), systemic
lupus erythematosus (Nordstrom et al., 1985),
osteopetrosis (Patel, 1987), Coats syndrome
`
(Goutieres
et al., 1999), mumps encephalitis
(Abrey and Walters, 1996) and Type 1 gangliosidosis (Chen et al., 1999). The number of cases
reported in some of these conditions has been
small, making for weak and often coincidental
correlations (see, for example, Sanfield et al.,
1986; Miladi et al., 1998; Stubgen

and Lotz,
1992).
Having found symmetric BGC in three children
with chronic active EpsteinBarr virus infection,
Morita et al. (1998) suggest that this infection
could cause the calcification that occurs in cases
of AIDS and in other idiopathic cases. Wilson et
al. (1996) described a 22-year-old schizophrenic
male with a history of solvent abuse and possible
adult Alexanders disease with histopathological
findings of BGC, Rosenthal fibers and frontotemporo-parietal demyelination. However, they
were unable to confirm a link between BGC and
either Rosenthal fibers or demyelination. Mousa et
al. (1987) described nine cases of BGC in their
sample of 65 cases of brucellosis. Four of their
nine cases manifested psychiatric symptomatology.
In a study of Raines syndrome (i.e. generalized
osteosclerosis, craniofacial anomalies and intracranial calcifications), Rickert et al. (2002) inversely
correlated mineral deposits with regional blood
circulation and capillary density. Halpern et al.
(1991) described BGC in 15 of 50 patients with
cretinism. In the most severe cases of the series,
calcification was the most relevant finding demonstrated by CT. The condition is associated with
mental retardation and both pyramidal and extrapyramidal signs. In a series of 37 patients with
scleroderma Heron et al. (1999) found 12 (32.4%)
with calcification of small arteries and arterioles,
primarily in BG. They also found a correlation
between BGC and duration of Raynauds phenomenon (Heron et al., 1998). Komatsu et al. (1992)
suggest that lesions of bilateral globus pallidus
may lead to abnormalities in monoamine metabolism. This condition could cause a neuroleptic
malignant syndrome-like state by compromising

the brain centers that control body temperature.
Presence of bilateral thalamic and BG calcification with diffuse atrophy in a 75-year-old woman
with an atypical senile dementia with overlapping
clinical symptoms of Alzheimers and Picks diseases led to the diagnosis of diffuse neurofibrillary
tangles with calcification (Narita et al., 2002).
Lesions predominated in the amygdala and caudate
nucleus with a distribution similar to that seen in
Picks disease (Tsuchiya et al., 2002).
Finally, BGC and Downs syndrome are closely
related, the association ranging broadly from
10.7% of the cases described by Ieshima et al.
(1984) to 45% of the cases of Takashima and
Becker (1985). Researchers agree that calcification
is more prominent with increasing age, a condition
probably related to abnormal vessels. In the past,
BGC has been associated with the premature aging
characteristic of Downs syndrome (Wisnieski et
al., 1982).
10. Basal ganglia mineralization and neuropsychiatric disorders
Modern studies have shown that psychiatric
symptoms are pervasive in patients with extensive
BGM. These symptoms include mood disorders,
organic hallucinatory disorders, obsessive-compulsive features, drug addiction, and personality and
cognitive dysfunction (Cummings et al., 1983;
Gluck-Venlaer et al., 1996). Since BGythalamo
cortical circuits damaged in BG diseases have
been related to depression and motor symptoms
(Sobin and Sackeim, 1997), some of the manifestations of BGM may therefore result from a disconnection syndrome. In this regard, LopezVillegas et al. (1996) evaluated 18 patients with
BGC. Four of them (22%) had mood disorders,
and six (33%) obsessivecompulsive disorder.
They report a pattern of neuropsychological
impairment consistent with BG damage affecting
fronto-limbic-BG circuits as described by Cummings and Benson (1984) and Cummings (1993).
They also described seven patients with epilepsy,
attributing calcification in five of them to the use
of anticonvulsive therapy. In the cases of calcification associated with anticonvulsant therapy, they
found less alteration in motor skills, probably

reflecting a different pathogenesis. Globally, all
subjects with BGC reported by Lopez-Villegas et
al. (1996) performed worse than a control group
in motor skills, executive functions, auditory verbal learning and visuospatial functions. This trend
persisted even after excluding patients with epilepsy and Parkinsonism.
Which individual manifestation becomes
expressed depends on the age of symptom onset
(Cummings and Benson, 1984; Chiu et al., 1993;
Konig,
1989; Konig
and Haller, 1982; Trautner et
al., 1988). In young individuals (2040 years),
the predominant neuropsychiatric manifestation is
a schizophreniform psychosis without neurological
features. If the initial manifestations occur later in
life (mean age at onset of 49 years), the presenting
symptoms are dementia and movement disorders.
Although the age of presentation seems to regulate
the type of symptoms expressed by affected
patients, the incidence of neuropsychiatric findings
is most dependent on the amount of mineralization.
Kazis (1985) reported that 50% of patients with
extensive brain mineralization exhibited mental
disorders compared to 34.5% of those showing
limited deposits.
When psychosis, dementia or mood disorders
are associated with movement disorders, clinicians
should consider the possibility of idiopathic BGM
(Chiu et al., 1993). Clinicians should also suspect
BGM in Downs syndrome patients with psychosis, levodopa-resistant Parkinsons disease, multiple system atrophy and progressive supranuclear
palsy patients, and certain familial cases of schizophrenia having an unusual sensitivity to neuroleptics (Berendes and Dorstelmann, 1978; Cohen et
al., 1980; Drayer et al., 1986; Francis, 1979;
Francis and Freeman, 1984; Klawans et al., 1976;
Thase, 1984; Wisnieski et al., 1982). If psychotic,
these patients may benefit from treatment with
lithium carbonate but not with neuroleptics (Munir,
1986). Laboratory examinations have shown
abnormalities of dopamine, iron and porphyrin
metabolism in such disorders (Savoldi et al., 1980;
Schmidt et al., 1988; Beall et al., 1989). Since
previous reports have not examined these parameters, it may be useful to screen for similar
abnormalities in suspected cases.
77
Several factors support the contention that any

relationship between BGM and schizophrenia
results from iron deposition (Blinder et al., 1986).
First, iron is distributed in a pattern similar to
dopamine (for a review, see Youdim and Yehuda,
2000). This is not surprising since iron acts as a
cofactor for the enzyme tyrosine hydroxylase.
Reactive iron (FewIIx) can catalyze the oxidation
of dopamine and convert H2O2 into the hydroxyl
radical via the Fenton reaction (Yantiri and Andersen, 1999). In addition, it is intriguing that chlorpromazine may exert its therapeutic effect by
chelating iron (Rajan et al., 1974) or by altering
the blood-brain barrier to enhance iron transport
to the brain (Ben-Shachar et al., 1993). Moreover,
variations in iron concentration selectively modulate the binding affinity of the dopaminergic (D2)
receptor as measured by w3Hxspiroperidol binding
(Ben-Shachar and Youdim, 1990; Youdim, 1985).
Csernansky et al. (1983) have demonstrated that
injecting ferric chloride into the amygdala of
rats produces apomorphine-induced behavior,
dopaminergic supersensitivity and increased
w3Hxspiroperidol binding in the caudate nucleus.
The dopamine abnormalities observed in patients
with BGM (Savoldi et al., 1980) may therefore,
link brain mineralization to iron and schizophreniform manifestations.
Dopamine does not appear to be the only possible mechanism by which alterations in brain iron
manifest symptoms. Iron colocalizes with gammaaminobutiric acid (GABA), serotonin (5HT) and
some neuropeptides, thus suggesting a role in the
utilization of these neurotransmitters (Hill et al.,
1985; Kobayashi et al., 1987). Iron is transported
in plasma by the protein transferrin, which is
synthesized locally within the brain in the choroid
plexus (Tsutsumi et al., 1989). Serotonin regulates
the expression of transferrin (Tsutsumi et al.,
1989). Contrariwise, iron deficiency leads to an
increase in serotonin (Mackler and Finch, 1982).
In addition, iron is a cofactor of oxidative phosphorylation enzymes (succinate dehydrogenese
and aconitase); it serves a similar function for
phenylalanine hydroxylase (Dallman et al., 1978;
Mackler et al., 1979; Pollitt and Leibel, 1976).
78
Derangements of iron metabolism may therefore, give rise to symptoms through a number of
different mechanisms whose interactions may be
difficult to predict and elucidate. Several neuroimaging studies have addressed the possible relationship between BG pathology, iron and
schizophrenia. Besson et al. (1987) found
increased BG TI signals in their schizophrenic
patients. Since the change was most pronounced
in those patients exhibiting tardive dyskinesia, they
concluded that any tissue pathology was due to
the presence of neuroleptics or to some other
change secondary to neuroleptic usage. Given a
previous case report of increased BGM in a patient
with tardive dyskinesia (Campbell et al., 1985),
Heinz et al. (1988) analyzed the signal intensity
(T2) associated with paramagnetic substances in
several subcortical nuclei of tardive dyskinesia
patients. The authors reported no significant findings in their patients with tardive dyskinesia. Since
the study lacked a control series, the results remain
inconclusive. More recently, Bartzokis et al.
(1990) reported significantly shortened left caudate T2 relaxation times in tardive dyskinetic
patients. The authors related the shortened T2
signal to the presence of an increased amount of
iron in this brain region. Bartzokis et al. (1997)
demonstrated aging-related increased tissue levels
of ferritin iron in BG in early onset Parkinsons,
Alzheimers and Huntingtons diseases. The findings are suggestive of an association between
increased iron levels, oxidative stress and neurotoxicity (Bartzokis et al., 1999a,b; Bartzokis and
Tishler, 2000).
The prevalence of incidental BGM discovered
by CT varies between 0.33 and 1.5% (Table 4).
In at least one series, Taxer et al. (1986) found
that the prevalence of psychotic symptoms in
patients with incidental BGM exceeded that of
the general population. Taxer et al. (1986) reported
endogenous psychosis in 11% of his patients.
Using a computerized image analysis system,
Casanova et al. (1990a) also quantified the area
occupied by minerals in patients with schizophrenia (ns7y275 or 2.54%) and a psychiatrically
impaired control population (ns11y450 or 2.4%).
They found no difference in either prevalence or
area of mineralization between the two groups.
Fernandez-Bouzas et al. (1990) studied a smaller

series of 45 schizophrenic patients. The prevalence
of mineralization in this study (ns4y45 or 8.8%)
far exceeded that reported for the general population. Interestingly, none of their patients with
bilateral mineralization improved after neuroleptic
therapy. Burns et al. (1990) reported mineralization in 21 out of 276 BG from 138 Alzheimers
patients (ns21y276 or 7.6%). Patients with BGM
and less ventricular enlargement were associated
with more complex or bizarre delusions. This
finding supported the association of BG and limbic
system disease with the development of delusions.
Haskins and Leslie (1992) report four patients
with BGC and psychiatric diseases in a sample of
262 patients from a mental institution (1.5%).
They report an increasing number of mood disorders in patients with BGC. McClellan et al. (1988)
reported two cases of BGC in a sample of 261
patients from a mental institution (0.76%). In this
sample, CT demonstrated abnormalities unrelated
to the admissions diagnosis in only four cases
(1.5%). The findings do not support routine
screening with CT in patients hospitalized for
psychiatric disorders.
Postmortem studies have failed to elucidate the
role of BGM in schizophrenia. Neuman (1963)
found a lower prevalence of BGM in psychiatric
patients at St. Elizabeths Hospital than that reported for the general population. Mulder and Denst
(1950) correlated only a slight reduction in the
number of neurons with widespread vascular calcification of the corpus striatum and cerebellum in
a 27-year-old woman who died after a 4-year
history of schizophrenia. Strassmann (1949)
reported 11 cases of calcification in his series of
280 autopsies (3.9%). Unfortunately, because he
did not specify a precise localization of the calcification, one cannot identify the incidence of this
finding in the BG. Other postmortem series have
also reported negative results (Hunter et al., 1968;
Casanova et al., 1990b). A more recent study
quantifying the staining intensity of iron in longstanding formalin-fixed tissue has shown increased
amounts of iron in the caudate of patients with
schizophrenia (Casanova et al., 1992). The authors
attributed this finding to a side effect of neuroleptic

usage.
Researchers have reported schizophreniform
psychosis in patients with Downs syndrome (Jakab, 1978; Thase, 1984). The coincidence of two
cases with similar pathology and clinical manifestations suggested that the BG lesion might increase
the likelihood that patients would develop schizophreniform symptomatology (Thase, 1984). Interestingly, the incidence of psychotic episodes (10%)
(Gibson, 1978) and BGM (7%) (Malamud, 1964)
is roughly the same in institutionalized patients
with Downs syndrome.
In summary, mineral deposition within the BG
and other brain structures occurs across a large
spectrum. Although most common in the globus
pallidus, in extreme cases this type of mineralization involves the putamen, dentate nucleus, cerebral white matter and cortex. Small accumulations
are asymptomatic. Extensive deposition of minerals may be a marker of an underlying pathological
process. Clinical symptoms can be progressive and
may include cognitive impairment, seizures, dysarthria, movement disorders, Parkinsonism, alterations of mood and psychosis. Both the frequency
and severity of mental deterioration, convulsions
and cataracts increase in proportion to the duration
of uncorrected metabolic abnormalities. Thus, all
symptomatic patients with BGM should be
screened for derangements in calcium metabolism.
Recent investigations have emphasized abnormalities of iron and dopamine metabolism in symptomatic patients with extensive BGM and a normal
calcium metabolism, e.g. no parathyroid abnormalities. In these patients, iron deposition antecedes calcium accumulation. Calcification is
therefore best considered a tombstone of the underlying process by which iron is deposited. Important
among the mechanistic explanations of tissue injury in BGM is free radical reactions for which iron
serves as a catalyst. Iron also acts as a cofactor
for the enzyme tyrosine hydroxylase. This fact
may help explain why iron codistributes with the
neurotransmitter dopamine. Free radical reactions,
iron deposition and dopamine abnormalities may
provide a link between BGM and psychotic
symptomatology.
79
Acknowledgments
This article is based upon work supported by
the Stanley Medical Research Foundation and
NIMH grants MH61606 and MH62654.
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Psychiatry Research 121 (2003) 5987

Mineralization of the basal ganglia: implications for

Department of Psychiatry, Medical College of Georgia, Augusta, GA 30912, USA

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

literature could help institute palliative therapy and

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

For the disorder

His jaw was firmly locked and his thorax was

Shortly after Fahrs case report, Fritzche (1935)

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

Speech Seizures Pyramidal ExtraCerebellar Cerebellar

Aiello et al. (1981)

Geyelin and Penfield (1929)

Moskowitz et al. (1971)

Ogata et al. (1987)

Equivocal plantar reflexes

Provides little clinical detail, SXRs

Glaucoma, microcephaly, loss of vision

Microcephaly, CSF pleocytosis

Short stature, SXR

Cerebral palsy, consanguinity

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

and surrounding glial cells (Kobayashi et al.,

he discovered them also in glia and neurons, where

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

followed by occipital, sensory and parietal cortex.

cification (DNTC), five with Alzheimers disease,

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

gression of mineral deposition within this matrix

authors believe excitatory amino acid receptors

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

5. Animal models of basal ganglia mineralization

cell loss, making it unlikely that this condition is

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

Towfighi et al. (1991) studied the amount of

mineralization with 515 times the sensitivity of

differences in sensitivity. Fenelon

Age range of cases

Koller et al. (1979)

1899 (mean 42.7)

984 (mean 43)

Haskins and Leslie (1992)

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

In a group of patients with BGC, Forstl

patients with BGC in their CTs (Forstl

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

reviewed by these authors, all patients over 45

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

correlated with hyperintensities in T2 and proton

with angiopathy. The normal perfusion probably

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

zation on CT scans by the age of 50 years, but

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

periods. One postmortem study showed no mineral

Kurup and Kurup (2002) described BGC in six

Familial idiopathic cases

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

M.F. Casanova, J.M. Araque / Psychiatry Research 121 (2003) 5987

ditions include unusual associations like neurocysticercosis

1986; Miladi et al., 1998; Stubgen