Journal of Neurology, Neurosurgery, and Psychiatry 1985;48:61-64

Basal ganglia calcification in Down's syndromeS TAKASHIMA, LE BECKER

From the Division of Neuropathology, Department of Pathology, University of Toronto, The Hospitalfor SickChildren, and Toronto General Hospital, Toronto, Ontario, Canada

SUMMARY The basal ganglia from 33 patients (all over one year of age) with Down's syndrome wereexamined pathologically. Forty-five per cent had calcification. Basal ganglia calcification was local-ised to a constant area of globus pallidus and became more prominent with increased age.Calcification and amyloid degeneration of the adjacent blood vessels were present. The proximityof abnormal blood vessels to basal ganglia calcification suggests a pathogenetic relationship.

Individual cases of basal ganglia calcification at nec-ropsy in Down's syndrome have been noted' 3 andrecently, basal ganglia calcification in patients withDown's syndrome was correlated on computedtomography and neuropathological examination(unpublished data).4 Basal ganglia calcification maybe a manifestation of premature ageing; however, itspathogenesis in Down's syndrome is not known.We reviewed the necropsies on patients with

Down's syndrome and examined brain tissue byneuropathological techniques, comparing degree ofbasal ganglia calcification, vascular amyloidosis,astroglial proliferation and neurofibrillary degener-ation.

Patients and methods

We reviewed the necropsies on the 228 Down's syndromepatients done at The Hospital for Sick Children and TorontoGeneral Hospital from 1963 to 1982. Of these, the 33 casesthat were older than one year and had good representativesections of basal ganglia were selected and their neuro-pathology examined. They ranged in age from one year to 60years. Clinical data were taken from clinical and/or necropsyrecords. The diagnosis of congenital heart disease was basedon the necropsy observations.

In addition to routine pathological examination of braintissue, Luxol fast blue, Bielschowsky, Van Gieson, Congored and glial fibrillary acidic protein (GFAP) (immuno-peroxidase reaction) stains of basal ganglia andBielschowsky stain of hippocampus were done. Histologicalseverity of basal ganglia calcification was graded as: negative(-), no basal ganglia calcification; borderline (±), single

Address for reprint requests: Dr LE Becker, Department ofPathology, The Hospital for Sick Children, 555 University Avenue,Toronto, Ontario, Canada M5G IX8.

Received 23 March 1984 and in revised form 20 June 1984.Accepted 25 June 1984

globules in some fields; mild (+), single globules in all fields;moderate (+ +), numerous deposits; and severe (+ + +),massive deposits. The severity of gliosis and neurofibrillarydegeneration was also graded as negative (-), mild (+),moderate (± +) and marked (++ +).

Results

(1) Basal ganglia calcificationThe relationship between age and grade of basal gan-glia calcification is shown in fig 1. The five cases withsevere basal ganglia calcification had massive clustersof branched and polycyclic calcium deposits in thebasal ganglia, predominantly at the medial side of thelateral medullary lamina of globus pallidus.' Calciumdeposits in putamen ranged from + to + + + (+ inthree, + + in one and + + + in one). Some cases hadmild deposits in the capsula interna. The perivascularcalcium droplets were of various sizes and mainlyaround small vessels. Vascular wall calcification wasevident in the large vessels (fig 2), particularly in themedia and adventitia of arteries. In the four patients

++

rs +

8

08 0

0 0 0

i0000 0

io io iyAge ( yecrs)

40 so 60

Fig I Relationship between basal ganglia calcification andage in Down's syndrome.

61

z

P&

group.bmj.com on November 8, 2017 - Published by http://jnnp.bmj.com/Downloaded from

Takashima, Becker

e

v*.p 40 o,.i.

-~ p,,e

Al.__~

0

40

;W

0 .0 o -* . .4v,Aw

V vo0.

4 9),: t, 0

*A4

4~~~~~

444-"-A4

4

Fig 2 Perivascular calcium droplets around small vessels and vascular wall calcification of larger arteries in globus pallidus.H&E stain, x 260.

between the ages of 45 and 60 years, there was intimalthickening and hyalinisation of the arterial wall. Twoof these four cases had old infarction in other parts ofthe brain. The adolescent had partial or completecircumferential calcification of elastic lamina in thesearteries.The three patients with moderate basal ganglia

calcification had numerous calcium deposits in thesame areas as patients with severe basal gangliacalcification. In these cases there was borderline-to-moderate calcification in the putamen andcalcification in the media of the arteries.

In the five cases with mild basal gangliacalcification, single calcium globules were seen aroundmany small vessels of the globus pallidus and in onecase there was calcification of the vascular walls. Cal-cium deposits in putamen showed borderline-to-mildcalcification (- in one, + in three and + in one).Nine cases had single globules surrounding some

small vessels of globus pallidus or putamen (border-line) and another 11 were negative.

(2) Congo red and GFAP stainsAll patients with moderate or severe basal gangliacalcification had some vascular calcification and amy-loid deposition in the vascular wall. In the patientswith prominent calcified vessels, all 29 years or older,amyloid deposits were apparent and in those withuncalcified vessels slight to moderate deposits wereusually seen in the media at the outside of the elasticlamina. A 26-year-old patient had mild amyloidangiopathy together with mild basal gangliacalcification. In three cases more than 49 years old theneuropathological diagnosis, was cerebral amyloid.angiopathy, due to widesprea&involvement.GFAP stain showed focal reactive astrogliosis in

areas of basal ganglia calcification (fig 3), but thedegrees of astrogliosis and basal ganglia calcificationwere not related.

(3) Bielschowsky stain of hippocampusNeurofibrillary degeneration was related to the age ofthe patients rather than the grading of basal ganglia

4v..:ya

6FAV.

Alloo -

*-4.4

* w9 -W

62

A.41" .0

0

0

M &a *.40 "A ob

group.bmj.com on November 8, 2017 - Published by http://jnnp.bmj.com/Downloaded from

Basalgagi cacfain in Dwn ssydoe 63

.,, AA¶4 ,w* s *4t-,' ', t ' o #

I.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~I

A.W~e e u

e-I~~~~~~~~~~~~~~~~~~~~~~-('

Fig3 Focal reae a s in aa of c ation re ob e i GFAPs, x a

>t- J Efi,,N+ > < tt i { . ><V> jK-S.-

*#; t n 4 Y it'-'a 4\ z;9d 4

t f tP , 1* Rl.Do,, "

Foaeactive^ asrgios inX are of caP,cto area eof' glbu ,a u GFA stai x IO

calcification. Neurofibrillary degeneration wasmarked in the patients older than 46 years and mild inthose from 10 to 45 years old.

(4) Calcification of the cerebellumFive cases had calcification in the wall of some vesselsin the white matter and dentate nucleus of the cere-bellum; three of them had severe basal gangliacalcification and two moderate calcification.Calcification was milder in the cerebellum than inbasal ganglia.

Discussion

Recently, basal ganglia calcification has been seen onCT in 26-7% ofcases (8 of 30 living Down's syndromesubjects aged 11 to 48 years)4 and 10-7% of cases (6of 56 living Down's syndrome subjects aged 0 to 37years) (unpublished data). Basal ganglia calcificationis detected in random populations by CT scanning in0-3 to 0-6% of cases,5 -1 which indicates that it ismore common in Down's syndrome than in the gen-eral population.

In comparison, Wisniewski et al4 reported thatbasal ganglia calcification was detected histologicallyin 100% of cases (massive deposits in 33%, moderatein 15% and mild in 52%). In our study, definite basalganglia calcification in Down's syndrome was presentin 45% (15 of 33 brains). We found the degreeincreased with age but Wisniewski et al4 reportedmore frequent basal ganglia calcification in the young-est and oldest Down's syndrome subjects.

Basal ganglia calcification in the normal populationis occasionally observed in older patients ( > 40 years).Slager and Wagner,7 in their histological study ofcalcium deposits within basal ganglia in unselectednecropsy patients, found an increased incidence withage. In Down's syndrome, basal ganglia calcificationappears at a younger age; perhaps it is an indicationof premature ageing.4

Histological and histochemical studies of basal gan-glia calcification have shown that the calcificationoccurs in the pericapillary and the media of smallarteries but the nerve cells generally remainunchanged. Slager and Wagner7 assumed that theprimary changes are compatible with pseudo-

63Basal ganglia calcification in Down's syndrome

group.bmj.com on November 8, 2017 - Published by http://jnnp.bmj.com/Downloaded from

64

calcification, which frequently involves the globuspallidus and dentate nucleus in old age and consistsof a primary deposition of extravascular acidmucopolysaccharide-alkaline protein complex. Sec-ondary precipitation of calcium and iron in the gelmay be the high density seen on CT.1' 12The pathogenesis of basal ganglia calcification in

Down's syndrome is unknown. According to Wis-niewski et al4 postmortem-detected basal gangliacalcification is more frequent in the youngest and old-est Down's syndrome subjects. They suggested that inyouthful Down's syndrome subjects it may be second-ary to cerebral ischaemia which may be due to con-genital heart disease; Ieshima and colleagues alsospeculated that it may be related to vascularinsufficiency in the globus pallidus or an undetectedmetabolic disorder (unpublished observations).We found basal ganglia calcification was localised

to a constant area of globus pallidus, calcification wasincreasingly severe with ageing and calcification andamyloid degeneration of the adjacent blood vesselswere present. This angiopathy was found not only incalcified arteries of old subjects, but also in uncalcifiedarteries of some young subjects. Three cases showedcerebral amyloid angiopathy, which might be anotherexample of premature ageing. Our findings suggestthat progressive structural change occurs in vesselwalls with advancing age. Moreover, GFAP stainsshowed reactive astrogliosis localised to the areas ofcalcification, which may be secondary to focal circu-latory disturbance due to the angiopathy. Nodifference in the incidence of basal gangliacalcification between patients with and those withoutcongenital heart disease was seen, suggesting thatfocal lesions associated with the angiopathy mayoccur because of a vascular structural abnormalitysuch as a vascular permeability disturbance ratherthan by systemic hypoxic-ischaemic events.

This paper was prepared with the assistance of theMedical Publications Department, The Hospital forSick Children.

Takashima, Becker

References

Murofushi K. Symmetrischer Pseudokalk in Stamm-ganglien und Grosshirnmark mit diskreter Leuk-encephalopathie bei Down'schem Syndrom. Neu-ropaediatrie 1974;5:103-8.

2Jakab I. Basal ganglia calcification and psychosis in mon-golism. Eur Neurol 1978;17:300-14.

3Merikangas JR, Marasco JAJ, Feczka WA. Basal gangliacalcification in Down's syndrome. Comput Tomogr1979;3:1 11-13.

4Wisniewski KE, French JH, Rosen JF, Kozlowski PB,Tenner M, Wisniewski HM. Basal ganglia calcification(BGC) in Down's syndrome (DS)-another man-ifestation of premature aging. Ann New York Acad Sci1982;396: 179-89.

'Barr ML, Kiernan JA. The Human Nervous System: anAnatomical Viewpoint. 4th edition, Philadelphia: Harper& Row, 1983.

'Murphy MJ. Clinical correlations of CT scan-detectedcalcifications of the basal ganglia. Ann Neurol1979;6:507-1 1.

7Slager UT, Wagner JA. The incidence, composition, andpathological significance of intracerebral vasculardeposits in the basal ganglia. J Neuropath Exp Neurol1956;15:417-31.

8 Koller WC, Cochran JW, Klawans HL. Calcification ofthe basal ganglia: computerized tomography and clinicalcorrelation. Neurology (Minneap) 1979;29:328-33.

9 Brannan TS, Burger AA, Chaudhary MY. Bilateral basalganglia calcifications visualised on CT scan. J NeurolNeurosurg Psychiatry 1980;43:403-6.

10Cohen CR, Duchesneau PM, Weinstein MA. Calcificationof the basal ganglia as visualized by computed tomo-graphy. Radiology 1980;134:97-9.

Adachi M, Wellman KF, Volk BW. Histochemical studieson the pathogenesis of idiopathic non-arterioscleroticcerebral calcification. J Neuropath Exp Neurol1968;27:483-99.

12 Lowenthal A, Bruyn GW. Calcification of the strio-pallidodentate system. In Vinken PJ, Bruyn GW, eds.Handbook of clinical neurology, vol. 6, Amsterdam:North-Holland Publishing Co, 1968:703-29.

group.bmj.com on November 8, 2017 - Published by http://jnnp.bmj.com/Downloaded from

Down's syndrome.Basal ganglia calcification in

S Takashima and L E Becker

doi: 10.1136/jnnp.48.1.611985 48: 61-64 J Neurol Neurosurg Psychiatry 

http://jnnp.bmj.com/content/48/1/61Updated information and services can be found at:

These include:

serviceEmail alerting

online article. article. Sign up in the box at the top right corner of the Receive free email alerts when new articles cite this

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.com on November 8, 2017 - Published by http://jnnp.bmj.com/Downloaded from