1. health and fitness
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Parkinsonism and Related Disorders 11 (2005) 73–80
www.elsevier.com/locate/parkreldis
Review
What is and what is not ‘Fahr’s disease’
Bala V. Manyam*
Department of Neurology, Scott & White Clinic, Plummer Movement Disorders Center, The Texas A&M University System Health Science Center
College of Medicine, 2401 South 31st Street, Temple, TX 76508, USA
Abstract
Bilateral almost symmetric calcification involving striatum, pallidum with or without deposits in dentate nucleus, thalamus and white
matter is reported from asymptomatic individuals to a variety of neurological conditions including autosomal dominant inheritance to
pseudo-pseudohypoparathyroidism. While bilateral striopallidodentate calcinosis is commonly referred to as ‘Fahr’s disease’ (a misnomer),
there are 35 additional names used in the literature for the same condition. Secondary bilateral calcification is also reported in a variety of
genetic, developmental, metabolic, infectious and other conditions. In autosomal dominant or sporadic bilateral striopallidodentate calcinosis
no known calcium metabolism abnormalities are known to date. Clinically, parkinsonism or other movement disorders appear to be the most
common presentation, followed by cognitive impairment and ataxia. When presence of movement disorder, cognitive impairment and ataxia
are present, a computed tomography scan of the head should be considered to rule-in or rule-out calcium deposits. Calcium and other mineral
deposits cannot be linked to a single chromosomal locus. Further genetic studies to identify the chromosomal locus for the disease are in
progress.
q 2004 Published by Elsevier Ltd.
Keywords: Fahr’s disease; Calcification; Basal ganglia; Bilateral striopallidodentate calcinosis; Parkinsonism; Ataxia
Contents
1. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
3. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
4. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
5. Neurophysiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
6. Neuroradiological features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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7. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76
8. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76
9. Proposed classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
76
* Tel.: C1 254 724 2766; fax: C1 254 724 5692.
E-mail address: [email protected]
1353-8020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.parkreldis.2004.12.001
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B.V. Manyam / Parkinsonism and Related Disorders 11 (2005) 73–80
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77
The brain is uniquely protected by the blood–brain
barrier from various toxins. Yet, the subcortical nuclei are
vulnerable to various minerals causing a variety of
disorders. Some examples include accumulation of copper
in Wilson’s disease, iron in Hallervorden-Spatz disease,
organic mercury in Minamata disease, and manganese in
parkinsonism. Calcification of basal ganglia and other
subcortical nuclei has resulted in a considerable dilemma
as to its significance and relationship to varieties of
neurological disorders. This article will attempt to review
the current knowledge on this ‘neuroradiological’ disorder
with views expressed on a proposed classification.
1. History
In 1850, Delacour first described vascular calcifications
of the basal ganglia in a 56 years old man who clinically had
stiffness and weakness of lower extremities with tremor.
Patient died of a short illness consisting of severe diarrhea,
hypotension and coma. Pathological examination showed
bilateral calcification and sclerosis. Having not seen similar
cases before, Delacour concluded that more research was
needed to understand this condition [1]. Bamberger
described the histopathologic entity of calcifications of the
finer cerebral vessels in 1855 in a woman who had mental
retardation and seizures [2]. In 1930, Fahr described an 81
years old patient with long history of dementia who
presented to the hospital with high fever, cough, decubitus
ulcer, ‘immobility without paralysis’ who was ‘bled and
given a purgative’ as treatment. Patient died three days later.
Examination of the brain revealed a ‘rough’ granular cortex
and lateral ventricles containing two spoonful of serous fluid
with calcifications in centrum semiovale and striatum [3].
Fahr’s name became associated with all forms of bilateral
calcifications in the basal ganglia and other parts of the
brain, despite the fact that he was not the first to describe
calcification in the brain nor did he contribute significantly
to the understanding of this disorder. Fritzsche gave the first
roentgenographic description of the condition in 1935 [4].
There has been a lack of consistent terminology when
reporting this ‘neuro-mineral’ disease. A plethora of
descriptive terms have been used to describe this disease,
with a total of 35 names, resulting in considerable confusion
as to what cases constitute this disorder (Table 1). Despite
popular reference, Fahr’s disease is a misnomer. As these
calcifications tend to show a predilection for the dentate
nuclei and basal ganglia, a descriptive term ‘Bilateral
Striopallidodentate Calcinosis (BSPDC)’ appears most
appropriate [40,41]. A detailed historical description is
given by Lowenthal and Bruyn [16].
2. Pathology
Pathological studies show that calcium is the major
element present and it accounts for the radiological
appearance of the disease. Mucopolysaccharides, traces of
aluminum, arsenic, cobalt, copper, molybdenum, iron, lead,
manganese, magnesium, phosphorus, silver, and zinc are
also present [16,22,42,43]. Calcium and other mineral
deposits were found in the walls of capillaries, arterioles,
and small veins and in perivascular spaces [22]. Neuronal
degeneration and gliosis surrounding these accumulations
have been reported [44]. Electron microscopy has shown
mineral deposits within the pericytes [34].
While the exact pathological process is not known, it has
been suggested that the hyperintense T2-weighted images
seen on magnetic resonance imaging (MRI) may reflect a
slowly progressive metabolic or inflammatory process in the
brain, which subsequently calcifies and is probably
responsible for the neurologic deficits observed [45]. It
has also been suggested that accumulation of iron and
calcium occur in response to the extravascular deposition of
an acid mucopolysaccharide–alkalic protein complex. MRI
studies have suggested that vascular membrane abnormalities may be responsible for the leakage of plasma-derived
fluid, and this, in turn, may damage the neurophil and result
in mineral accumulation [36].
While the exact reason why the basal ganglia is
vulnerable for calcium deposits has not been established,
it appears that the basal ganglia is a target for many other
deposits in addition to various minerals. These non-mineral
substances include bilirubin in the newborn, especially preterm babies leading to kernicterus, MPTP and carbon
monoxide poisoning leading to parkinsonism.
3. Genetics
BSPDC manifests as autosomal dominant, familial and
sporadic forms [7,18,19,21,24,25,28–30,35–38,46–53].
While autosomal dominant and sporadic forms need no
further clarification, the term familial is used based on the
Stedman’s Medical Dictionary [54] to denote affecting more
than one member in the same family that can be accounted
B.V. Manyam / Parkinsonism and Related Disorders 11 (2005) 73–80
Table 1
Terms in the literature to describe bilateral calcification involving striatum,
pallidum and dentate nucleus
Year
Descriptive term
1939
1943
Symmetric cerebral calcification [5]
Gross calcareous deposits in the corpora striata and
dentate nuclei [6]
Calcification of the carpus striatum and dentate nuclei
[7]
‘Idiopathic’ calcification of cerebral capillaries [8]
Symmetrical calcification of the basal ganglia [9]
Familial calcification of the basal ganglia [10]
Calcification of the basal ganglia of the brain [11]
Familial idiopathic cerebral calcifications [12]
Idiopathic nonarteriosclerotic calcification of cerebral
vessels [13]
Familial bilateral vascular calcification in the central
nervous system [14]
Nonarteriosclerotic idiopathic cerebral calcification
of the blood vessels [15]
Calcification of the striopallidodentate system [16]
Idiopathic familial cerebrovascular ferrocalcinosis
[17]
Familial calcification of the basal ganglions [18]
Familial idiopathic basal ganglia calcification [19]
Symmetrical calcification of brainstem ganglia [20]
Familial idiopathic cerebral calcifications [21]
Striopallidodentate calcifications [22]
Pallido-dentate calcifications [23]
Familial calcific dentato-striatal degeneration [24]
Familial basal ganglia calcification [25]
Fahr’s syndrome [26]
Idiopathic familial basal ganglia calcification [27]
Idiopathic calcification of the basal ganglia [28]
Progressive idiopathic strio-pallido-dentate calcinosis
[29]
Idiopathic familial brain calcifications [30]
Calcification of the basal ganglia [31]
Symmetrical intracranial advanced pseudocalcium
[32]
Bilateral-symmetrical calcification of basal ganglia
[33]
Idiopathic nonarteriosclerotic cerebral calcification
[34]
Familial idiopathic striopallidodentate calcifications
[35]
Idiopathic cerebral calcifications [36]
Familial idiopathic strio-pallido-dentate calcifications
[37]
Familial idiopathic brain calcification [38]
Idiopathic basal ganglia calcification [39]
1951
1954
1957
1957
1959
1960
1961
1964
1966
1968
1969
1971
1974
1976
1977
1977
1978
1979
1979
1982
1983
1983
1983
1984
1985
1985
1986
1987
1989
1989
1993
1997
1997
Numerals in brackets denote reference number.
for by chance but not to mean ‘genetic’. Whole-genome
scan of a large autosomal dominantly inherited pedigree,
polymorphic microsatellite markers were used to identify
the first chromosome locus. This resulted in identifying the
locus on chromosome 14q48 [55]. Smits et al. [29] reported a
family of one female and two males in the second
generation with their father’s death being secondary to
‘stroke’ and autopsy showed no intracranial calcification.
Age at death was not mentioned and the mother had a
normal clinical examination and CT scan. Eleven of 14
75
members of the third generation, with the age range of 5–15
years, had normal clinical examinations and computed
tomography (CT) scans. The authors concluded that the
inheritance was autosomal recessive. But, they failed to give
adequate evidence to arrive at such a conclusion. It more
clearly fits into familial pattern. In another report [56], a
single family of four generations with 23 members was
described in which the authors suggested the pedigree to be
x-linked. However, there were two female transmissions
and one male transmission. Thus, it did not meet the criteria
for x-linked dominant pattern, but rather fitted into an
autosomal dominant pattern of inheritance. Having asymptomatic parents is not adequate in concluding that a person
is sporadic. In addition, CT or MRI scan or neuropathological evidence showing the absence of bilateral, almost
symmetric calcification in the brain is necessary. Also, it is
necessary to have negative CT or MRI scans in all adult
siblings and children. Similar criteria apply to the familial
form, except that more than one member in the family is
affected, and the person must not be either a parent or
offspring of the person affected.
4. Clinical features
BSPDC is a rare disorder. Clinical distinction of BSPDC
has been blurred by a variety of factors. Clinical
manifestations of BSPDC are reported in the literature as
individual case reports or as single-family reports due to the
rarity of the disease. Applying uniform criteria, cases
reported in the literature (nZ61) were combined with the
patients seen in a registry [46]. This combined data revealed
that of the 99 patients with proven calcium deposits, 67 were
symptomatic with a meanGSD age of 47G15 and 32 were
asymptomatic with a meanGSD age of 32G20.
The male:female ratio was 2:1. The most common
manifestation of BSPDC was movement disorders (55%)
of which Parkinsonism accounted for over half of all
movement disorders, while the hyperkinetic movement
disorders (chorea, tremor, dystonia, athetosis and oro-facial
dyskinesia) accounted for the rest. Cognitive impairment
was the second most common manifestation followed by
cerebellar impairment and speech disorder. Overlap of
neurologic manifestations such as hypokinetic movement
disorder associated with cognitive impairment and cerebellar signs were often present. Other minor overlapping
neurologic manifestations included pyramidal signs, psychiatric features, gait disorders, sensory changes and pain.
5. Neurophysiological studies
Electroencephalogram, nerve conduction studies, and
pattern shift visual-evoked potentials studies are generally
normal. Brainstem auditory-evoked potentials may vary
from normal to minor abnormalities, such as an increase in
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B.V. Manyam / Parkinsonism and Related Disorders 11 (2005) 73–80
inter-peak latencies from waves I to V or an increased wave
V latency. Somatosensory evoked potentials are generally
normal [41,57].
6. Neuroradiological features
Prior to the widespread availability of CT scan, case
reports of BSPDC were based on either skull roentgenogram
or autopsy. Since the advent of the head CT scan, the
number of case reports of intracranial calcifications has
increased, ranging from minimal calcification of the globus
pallidus in otherwise normal elderly individuals to cases
with massive calcification similar to those reported here. CT
scan is considered more sensitive than MRI for finding
deposits in BSPDC [41]. When a large number of CT scans
were screened (19,080 scans in three studies), the incidence
of basal ganglia calcifications ranged from 6 per 1000 to
7.49 per 1000, with an average of 6.6 per 1000 [57–59]. The
vast majority of these calcifications were quite small and
usually confined to the globus pallidus.
Calcification in the brain was almost symmetrical and
was seen in the dentate nucleus, basal ganglia, thalamus, and
centrum semiovale. Calcification elsewhere was rare. In
general, basal ganglia, dentate nucleus, thalamus, and
centrum semiovale were the regions most affected. No set
pattern was seen in a given family or group. In one study,
measurement of the amount of calcium was made using CT
scan in 31 patients. No significant right or left hemispheric
differences were noticed. The mean (GSEM) total areas of
calcification were: basal ganglia 1.39G0.28 cm3; thalamus
0.26G0.06 cm3; dentate nucleus 1.02G0.34 cm3; centrum
semiovale 0.64G0.22 cm3; totaling to 3.16G0.64 cm3. No
significant difference was found when the amount of
calcification was compared between autosomal dominant
symptomatic (nZ15) and asymptomatic (nZ12) groups
(meanGSD age, symptomatic group 54G17 and asymptomatic 44G17, respectively). The difference in age was not
significant. Symptomatic patients had a substantially greater
amount of calcification in all regions, with statistically
significant differences in dentate nucleus, centrum semiovale and sum-total [60].
Using 99mTehexamethyl-propylenamine oxime
(99mTc-HMPAO), single proton emission computed tomography (SPECT) revealed markedly decreased perfusion to
the basal ganglia bilaterally with decreased perfusion to the
cerebral cortices in BSPDC [61]. Positron emission
tomography scan using fluorodopa did not show any
significant difference between BSPDC patients and control
subjects [41].
7. Diagnosis
The features of BSPDC can be varied and the diagnosis is
established by obtaining a CT or MRI scan of the head
and ruling out abnormalities of known calcium metabolism
and developmental defects. Despite ease of availability of
CT and MRI scans, and the incidental finding of bilateral
calcium deposits in the subcortical nuclei in asymptomatic
patients, it is still rare. When parkinsonism is associated
with dementia and cerebellar signs, obtaining a CT scan
may be helpful, as BSPDC often presents with the above
three conditions. The major differential diagnosis is
hypoparathyroidism. Obtaining serum calcium and parathormone levels should help differentiate the two when CT
or MRI scan of the head shows bilateral striopallidodentate
calcification. Other possible conditions that show bilateral
subcortical calcifications in the brain are listed in Table 2.
These conditions may also be accompanied by varieties of
other neurological manifestations. The minimum age at
which a negative CT scan excludes the disease is not
established. One study [125] suggested decreased levels of
CSF calcium, without alterations of serum calcium, serum
and CSF phosphorus and albumin in bilateral striopallidodentate calcinosis.
8. Treatment
Selective removal of deposited calcium from the brain
without effecting calcium from bone and other tissues
appears to be an impossible task. Further, while calcium is
the major mineral deposited, there are several other minerals
are also deposited. Treatment with central nervous systemspecific calcium channel blocking agents like nimodipine
was unsuccessful (Manyam, unpublished). Reduced 25-OH
vitamin D3 with normal levels of 1,25(OH)2 vitamin D3,
suggest an inborn error of vitamin D metabolism in three
members with autosomal inheritance, bilateral striopallidodentate calcification and movement disorder [37]. Further
evaluation of this finding is needed to find a therapeutic
solution. In one patient, disodium etidronate showed
symptomatic benefit without reduction in calcification
[126]. This needs to be evaluated in a larger number of
patients by controlled studies.
9. Proposed classification
The proposed classification (Table 2) is based on the
anatomical sites where the calcium and other minerals are
deposited where almost symmetric sub-cortical calcifications occur, namely, bilateral striopallidodentate calcinosis,
striopallido (‘basal ganglia’) calcinosis, and dentate (cerebellar) calcinosis. Each of these classifications is divided
into sub-groups according to etiology; i.e. autosomal
dominant, familial, sporadic, and secondary causes. Classification of these disorders may be important in order to
understand the possible biochemical defect in mineral
binding that results in deposition of calcium and other
minerals in the sub-cortical nuclei. In the secondary causes,
B.V. Manyam / Parkinsonism and Related Disorders 11 (2005) 73–80
Table 2
Proposed classification of bilateral calcification involving striatum,
pallidum and dentate nucleus
Striopallidodentate calcinosis
Primary
Secondary
Endocrinologic
Developmental
Connective tissue disorders
Toxic
Autosomal dominant [7,18,21,24,
25,35,37,38,47,48]
Familial [19,29,30,49]
Sporadic [28,36,50–53]
Hypoparathyroidism [62–64]
Pseudohypoparathyroidism
[65–67]
Pseudo-pseudohypoparathyroidism [66,68]
Hyperparathyroidism [69–71]
Cockayne Syndrome [72–74]
Syndrome of microcephaly,
demyelination, and striopallidodentate calcification [75]
Systemic lupus erythematosus
[76–78]
Lead [79–81]
Bilateral striopallidal (‘basal ganglia’) calcinosis
Physiological
Aging. Over 50 years [57,58,82]
Developmental
Angiomatous malformation with
vein of Galen aneurysm [83]
Down’s Syndrome [84,85]
Oculocraniosomatic disease
(Kearns–Sayre Syndrome) [86,87]
Degenerative
Aicardi–Goutieres syndrome [88,
89]
Coat’s disease [90]
Diffuse cerebral microangiopathy
[91]
Hyperkinetic mutism [92,93]
Genetic
Biotinidase deficiency (AR) [94]
Carbonic anhydrase II deficiency
(osteopetrosis, renal tubular
acidosis and basal ganglia calcification, AR) [95–97]
COFS syndrome with familial1;16
translocation (AR) [98]
Lipomembranous polycystic
osteodysplasia (AR) [99,100]
Tapetoretinal degeneration (AD)
[101]
Infectious
AIDS [102,103]
Ch. active Epstein–Barr virus
infection [104]
Meningoencephalitis [105]
Mumps encephalitis [106]
Metabolic
Dihydropteridine reductase
deficiency [107–109]
MELAS syndrome [110–112]
Post-hypoxic/ischemic [113–115]
Neoplastic
Acute lymphocytic leukemia [116]
Physical agents
Radiation therapy [117–119]
Toxic
Carbon monoxide poisoning
[120]
Bilateral cerebellar calcification
Primary
Secondary
Infection
Vascular
Idiopathic [121,122]
Syphilis [123]
Hematoma [124]
Numerals in the brackets represent reference number.
77
listed in Table 2, the bilateral calcifications do not always
occur in all patients of that particular disease.
10. Conclusion
With the 35 names being used in the literature (Table 1),
it is best to avoid the term Fahr’s disease. As there are a
large number of disorders where bilateral calcification
occurs in the subcortical region, it is best to use the
anatomical location of the calcium deposits such as
striopallidodentate, basal ganglia (striopallido) or cerebellar
(dentate) calcinosis. While several minerals could be
present in addition to calcium, it is the latter that is
radiopaque and is present in the largest amounts, justifying
the term ‘calcinosis.’ The calcium and other mineral
deposits cannot be linked to a single chromosomal locus.
Geshwind et al. [55] found the autosomal dominant form
with neurological disease to 14q in one large family.
Brodaty et al. [127] excluded such a locus in the absence of
neurological, cognitive and psychiatric symptoms. Further,
in hypothyroidism the locus is on 11p [128], in pseudohypoparathyroidism it is on 20q [129], in Down’s syndrome it
is on 21q [130], excluding the possibility that a single gene
is responsible for the calcium and other mineral deposits.
Acknowledgements
Sincere thanks to Melissa Crchova, MD and Christine K.
Johnson for translation of German and French articles.
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