What is and what is not ‘Fahr's disease’

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5. Neurophysiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6. Neuroradiological features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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8. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9. Proposed classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* 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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10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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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

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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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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.

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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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