Original article184

Contribution of Magnetic Resonance Imaging in theEvaluation of Microcephaly*

By M. Stainlin, M. Ziiner, E. Maftin, Ch. Boesch, R. H. Largo and E. BoltshauserChildren's LJnivcrsitl, I lospit.al, CI I 8032 Ziirich, Su'itzerland

Magnetic resonance imaging (MRI) was per-formed in 33 children using a 2,35T MII system. The inten-tion was to determine the various types of morphological ab- rnormalities seen in primary microcephaly and the frequencywith which they occur. MRI findings were typical for clto- 1megalovirus infection in six patients. Cerebral malforma-tions were found in 14 cases and patchy white matter lesionsin both hemispheres in two subjects. Ml{I appeared to be ab-normal in eight of the remaining 1l children. However, weu'ere unable to provide an exact interpretation of the find-ings. All the children with MRI abnormalities with the excep-tion of two were neurodevelopmentally deviant. Thus, MRIrevealed abnormalities in the majority of infants with prima-ry microcephaly and neurodevelopmental disturbances. Itappears to be more sensitive than cranial ultrasound andcomputed tomography.

Key words

Microcephaly - Magnetic resonance imaging - Malformations - Myelination disorders - C1'tomegalo-virus infection

Abbreviations

MRI: Magnetic resonance imaging, CT:computed tomography, CMV: Cltolomegalovirus, T: Tesla

Microcephaly refers to a heterogeneous groupof disorders having a small head size as the common denomina-tor. In a simplified manner one can distinguish between primary"developmental" microcephaly and secondary "destructive"microcephaly, the latter being due to encephaloclastic processesof ischemia, infections or of toxic origin. "Microcephalia vera"is commonly used to designate a heterogeneous subgroup of de-velopmental microcephaly, in which the brain is generally wellformed but small.

There are scant reports on the significance ofcomputed tomography in the evaluation of microcephaly (6),and we are not aware of any study having used magnetic resonance in the evaluation of primary microcephaly. Magnetic res

Received l\'tay 23, 1990; accepted July 12, l!)90

Neuropedial . r ics 22 (1991) 18.1 lUg@ I lippokrates Verlag Stuttgart

onance imaging (MItl) allorvs a more accurate analysis of cere-bral anatomy and the process of myelination in vivo than ultra-sound and computed tomography (5, 7\. This study rvasdesigned to ascertain types and frequencies of abnormalitiesseen in MI{I in neurodevelopmentally disturbed children withprimary microcephaly and to determine rvhether the informa-tion obtained would be helpful for etiological u'ork up orwhether a clinicai pattern could be a prediction for certainneuroradiological findings.

Patients and methods

During the period 1986-1989, 33 childrenwith the diagnosis of microcephaly underwent MRI. Fifteenchildren were referred to our hospital for evaluation of micro-cephaly, of which five had in addition dysmorphic features. Sev-enteen others were referred primarily for neurodevelopmentalproblems. One child underwent the examination during theneonatal period because of microcephaly, dysmorphic featuresand neurological abnormalities.

'fhe criterion used for

microcephaly was a head circumference below the third percenti le (9).

In Figure I the reduction of head size is demon-strated by standard deviation scores. Patients u'ith secondarymicrocephaly as a result of asphyxia, trauma, intracranialhaemorrhage or meningo-encephalitis were exciuded. Therewere 18 female and 15 male patients, ranging between neonatesto seven years. Thirty subjects were less than three years old,nine subjects were reexamined, because of uncefaintv in the in-le rpre la l ion o f the f i rs t imag ing ser ies .

The children were sedated for the examinationby mild drugs such as chloralhydrat ( 100 mg/kg body weight)and./or Flunitrazepam (0.05 mg/kg body weight) given eitheroraily or rectally. T1 (SE 500/30) and T2 (SE 3000/120)weighted images were performed on a 2.35

'l-esla super-

conducting Ml{-system using a 256 x 256 imaging matrix ( 1 ).AII the MRI imagings were evaluated for gross morphology ofthe brain, gyral pattern and corlical architecture, the stage ofmyelination (8) and ventricular size.

Thifty-one children had a complete neurological examination. Sixteen of them underwent additional de-velopmental tesling (Gr|ffith's test [,1] or Snijders-Omennonverbal intelligence test [10]). Thirteen children had evi-dence of severe development.al delay, while t'"r,o children wereapparently normal. Two children \r''ere seen only during theneonatal period and thereafter lost to follow-up.

* Supporled by Swiss Nal.ional I'-oundation grant No.: 3.917 0.88 and 382.10 .87 .

- - ' l

4!{rcqt. , . , ^ ^

323130292A27262524

21

-oE 1 82 1 6

6 1 4v 1 3

1 21 11 0

87

4

21

\l RI in ,\lit rot:e[,ltt.rly

0 - 1 - 2 - 3 - 4 - 5 - 6 - 7 - 8 - 9

Fig. 1 Head crrcumference standard deviat ion scores

Results

Based on the \,1R1 findings the patients *,ere di-vided into tour groups: group A u-ith congcnital CN{\'infection,group I1 including cerebral malformations and/or m\relinationdisordcr, group C u'ith unclassifiable pathological findings andgroup D u'ith normal f indings.

GrotQ A

The results are summarized in Table 1. Sixchilclren had findings tlpical of congenital CN{\' infection (2):Paraventricular o.stic lesions adjacent lo the occipital horn ofthc lateral r'entricles and separated onl1. bt, a thin membrane

\eurofediatics 22 (1991 ) 1u5

(n : 5), oligo- and/or pachl'g1.ria combined rvith patchy d1'srnyelination and or general myelination delays (n : ,1), enlargedr,entricles and subarachnoid spaces (n: 3) (Fig. 2).

In three, out of six children. evaluation u'asperformed immediat.ely after bifth because of congenital microcephaly.

'Ihe other three der.eloped microcephaly during the

first 1.ear of life. Investigations rvere carried out at seven andtu elve months respectively. All six children presented r.vith cere-bral palsl'and ser.ere developmental delay. In three cases im-paired hearing lvas detected, rvhile in trvo children there.,vereassociated epileptic seizures.

Group B

In 16 children, r'arious malformatrons \\'ereidentified as a cause for the microcephaly, the results being summarized in Table 2.

In 10 children the follorving structural disor-ders u'ere found in various combinations: hrpoplasia oragenesis of the corpus callosum in nine, partial hlpoplasia oflhe cerebral hemispheres in tlrree (asymmetrical in t"vo cases,frontalll-in one) and diffuse hypoplasia of the cerebrum in tu'opatients. 'Ihe

cerebellum (hemispheres and./or r.ermis) rvash1'poplastic in six children rvhile in tu'o patients the brainstemrvas hl.poplastic. ln two cases these morphological disordersrvere found in cornbination lrith a Dandy-Walker-r,ariant rnai-formation (Fig. 3). In tu'o others a complex malformation of the'n'hole brain u'ith hlpoplasia of cerebrum, cerebellum andbrainstem u.as evident. A common finding in this group of malformations u'ere enlarged cerebral spinal fluid spaces, especiallr.of the ventricles associated lvith hlpoplasia of the cerebrum,colpocephaly associated u.ith hlpoplasia of the corpus callosumand enlargement of the infratentorial cisterns and of the 4thventricle u'ith cerebellar hlpoplasia.

Of three children shou'ing tl.pical pachyglriarvith thickened cortex and oligogr.ria or lissencephaly, tu'o hada parieto-occipital predominance (Fig. ,1), rvhile one had a dif-fuse pattern. Tr,vo children had schizencephall.uith deep gyriand the cortical mant.le reaching the r.entricles or basal ganglia.

Table 1 Group A Pat ents w th congeni ta CMV- nfect on

Agemon ths

I 2

r /2

Sex M crocephalycongenrta l

IVIRII nd rngs

paravenl tcu ar cystsmyel inat on defectsen arged ventr c es

paraventr icular cystspachygyna, myel inat ondefectsen la rged ventr ic les

paraventrcu ar cystsen arged ventr ic escal losa hypop asra

paraventr icular cystsmmature gyral pat tern

paraventr cular cystspachygyr ia, myelrnat ondefectsen la rged ventr ic les

myel inat on defectsDandy Walker variant

C in cal symptomsCP deveiop ep lepsy impa i red hea r ngoeray

yes

+ + +

T T T

+

T - T

T T T

- T T

+

T T TBO

186 Nailropediatrirs 22 (1991) M. Steinlin et al

Fig.2 Paraventricular cyst adjacent to the rightoccipital horn of lateral ventricle (arrow), separat-ed by a thin membrane. Pachygyria with predomi-nance paraeto-occipital and patchy myelination de-fect. Enlarged ventricles. M Rl -T2-weighted (3000/120) axial section, Case 2 group A, 7 months.

Fig. 3 Dandy-Walker variant with smail cerebel-lum and opening of the iourth ventr icle into thecisterna magna, cal losal hypoplasia. MRI-T1-weighted sagittal section (500/30), Case 15o r n r r n R 6 m n n t h q

Fig. 4 Pachygyria parieto-occipitally. MRI-T2-weighted (3000/120) axial section, Case 19o r n r r n R R m n n t h c

Table2 Group B: Patients with malformation andlor myelination disorders.

Case Sex Agemonlns

3 1

26

IV]RIf indings

^ ^ i l ^ ^ ^ t L . , - ^ ^ t ^ ^ i ^ud i luJdr i l yPUprd) td

hypoplasia optical radiat ioncerebral hemihypoplasiaasymmetrical hydrocephalusDandy-Walker variant^ ^ i l ^ ^ ^ t L . , ^ ^ ^ t ^ ^ i ^uoi luJdr i lypuprdsrd

cal losal hypoplasra, colpocephalyhydrocephalus internus

cerebral, cerebellar, callosal hypo-plasra

rudimentary anlage of the braincal losal hypoplasia, colpocephalysmali frontal lobes

cerebellar, cal losal hypoplasiahypoplasia r ight hemisphereand optical radiat ion

cal losal and vermis hypoplasiaperiventr icular calcif icat ionl issencephaly occipital

Dandy-Walker variantcal losal hypoplasia, enlarged ven-triclespachygyria

schizencephaly occi pital

myelination disorder centrumsemtovalepachygyria pa rieto-occi pitalpacnygynacallosal hypoplasia, colpocephalygyral disorder parieto-occipitallygl iosis nucleus caudatuspatchy dysmyelinationlack of myelination frontal ly

Clinical symptomsCP develop, delay eprlepsy other malJormations

10

1 1I2

13

I4

15

161718

1920

2 1

22

32

844

13

2 I

T T+

n I/2

m 9

T

+++

+++

+++

T T

+

+

+++

+++

+++

+++

T T

+++

++

+++

T T

+++

++

+++

+++

+++

palatoschisiscorneal cloudingmicrophthalmy

dysmorphic signs

chromosomal defectcardial malJormationfused ribs

renal insuff iciencydysmorphic signspers, art. hyaloideapersistentductus Botalli

mm

MKI in Microcefhaly Nauropadiatrics 22 (1991) 187

Fig. 5 Lack of white matter with folded cortex, enlarged supravermiancistern. MR|-T2-weighted (3000/120) axial section, Case24 groupC,4 months.

In four children, there was evidence of amyelination disorder. Two of the MRI showing pachyg5,'riawerecharacterized by tlpical patchy white matter lesions, probablydue to a primary lack of myelination. The other two infants re-vealed spots of disturbed myelination in the frontal lobe andcentrum semiovale; one of them had in addition, diffuse poormyelination of both frontal lobes.

Fifteen of the 1 6 children in this group sufferedfrom a variable kind and degree of cerebral palsy and develop-mental delay and six of them had epileptic seizures. One child(No. 11, Fig. 1) with a severe cerebral malformation and signifi-cant microcephaly, was neurologically normal at birth. He waslost to follow-up, but was most likely to be impaired in his fu-ture development.

Six of the children revealed dysmorphic fea-tures, while another six had ocular, cardiac or skeletal malfor-mations.

Table 3 Group C: Patients with unusual f indings.

Fig. 5 Patchy dismyelination occipitally (arrows). MRI-T2-weighted(3000/120) axial section, Case 28 group C, 25 months.

Group C

Atl the MRI evaluations of this group appearedabnormal, although an interpretation was not available. The re-sults are listed in Table 3. Three findings were suspicious of alack of white matter with decreased distances between the ven-tricles of basal ganglia and cortex. In these cases the gyral pat-tern appeared to be more deeply folded than usual (Fig. 5).

In three children the T2-weighted imagesshowed small h5,perintense patches of white matter - para-ventricular in the occipital lobe in two instances and once in thesubcortical region (Figs. 6 and 7).

Three imagings were characterized by a thick-ened cortex, combined with a clumsy gyral pattern (Figs.7and 8), however, neither of them fulfilled the criteria for pachy-g5,nia or oligogyria.

Sex Agemonths

IVRIf indings

hypoplasia of frontal lobes

enlarged cisterna magnalack of white matter

enlarged cisterna supracerebellarissmall splenium (colpocephaly)lack of white matter

small splenium, colpocephalysubcort ical dysmyelinationclumsy gyrl

unusual proport ion of hemispheresthick cortex, clumsy gyri

patchy dysmyelination occipital

enlarged cisterna magnadysmyelination occipital lythick cortex, clumsy gyri

thick cortex, clumsy gyri

Cl inical f indingsC P develop. delay

+++

+

+

T T

+++

epilepsy other malformations

Turricephalusfusion of 2 r ibsprominentears

Trichothio-dystrophy

(dysmorphic signs)

prominent ears

dysmorphic signs

24

25

18

4027

m

m

2829 +

2536

7y

188 Neuropediatrics 22 ( I 99 I ) M. Stainlin et al

Fig.7 Small splenium (arrow) with colpocephaly. Subcortrcal dis-myelination, most evident in r ight frontal lobe. MRI-T2-weighted (3000/I20)axial section, Case 26group C, 18 months.

Fig. 9 Hypoplasia of frontal lobes. MRI-T2-weighted (3000/t2a) axialsection, Case 23 group C, 6 months.

Fig. 8 Unusual proportion of the hemispheres with f lattened frontal andtapering occiprtal lobes. Thick cortex and clumsy gyri. MRl-T2-weighted(3000/120) axjal section, Case27 group C, 40 months.

The corpus callosum of two children was shortand small in the splenial part, accompanied by slightly enlargedposterior horns ofthe lateral ventricles (Fig. 7).

In one case atlpical proportions and forms ofthe cerebral hemispheres with tapering occipital lobes and flat-tened frontal lobes was noted (Fig. 8), while in another h1,po-

Table 4 Group D: Patients with normal f indinss.

plasia ofthe frontal lobes was seen (Fig. g). In four children un-usual findings in the posterior fossa such as enlarged cisternamagna or cisterna supracerebellaris were detected. All the chil-dren in this group with the exception of one had developmentalproblems. Five children had associated cerebral palsy and twohad epilepsy. In six out of eight cases, dysmorphic feature ofvarying degree were manifest. In one instance it was possible todetermine a known slrrdromal disorder.

Group D

Only three children, listed in Table 4, had anapparentiy normal MRI. Two of them suffered from develop-mental problems, one combined with cerebral palsy, while onechild developed normally during the study period.

Discussion

The population studied consisted of a selectedgroup of microcephalic patients, most of them with neuro-developmental disturbances, and referred for further evalua-tion. In 33 children with microcephaly as the major diagnosisMRI revealed the presence of pathotogy in 22 cases (67 Vo).Prior knowledge about morphological abnormalities is not onlyhelpful establishing diagnosis, but also for genetic counselingand in some situations enables one to predict the prognosis.

The relatively iarge number of CMV infectionsin group A is a result of an earlier study, describing tlpical MRIfindings in congenital CMV infection (2). Two children had con-genital CMV infection as a cause for the microcephaly, sero-

Sex IVl RIf i nd i ngs

Agemontns

Cl in ica l f ind ingsdevelop. delay other maltormations

3 13233

m

mf

normal

normal

normal

+++

+ dysmorphic signsdysmorphic signs

eprlepsy

I I Rl in,tr1ic roc eP h ul.v

togically proved in the neonatal period. ln the other four cases

Ctr{V infection was the most likely etiologl,- based on clinical

and serological findings. The NII{I changes rvere in agreementrvith prenatal CNI\,' infection. All six children were severel-y

handicapped u'ith cerebral palsy and developmental delay.Therefore. er,en u'hen there is no treatment for these childrenand the prognosis remains uncettain, the correct diagnosis is

crucial to rule out a risk of recurrence.

All the children (lvith malformation and/or

markedly disturbed myeiinatlon) in group B lr'ere severely men-

tally retarded and had cerebral palsl', usualll' spastic tetra-paresis. Obviouslj' the final outcome and the degree of handicap

in these children is only s1.i4gnt after a prolonged period of ob'

sen ation. The tlpe and severity of cerebral malformation u'as

heterogeneous and there was no correlation u'ith severity of

neurodevelopmental disturbances. Howe\,er, Mltl is helpful (in

broad terms) in situations .'r'hich empirically lead to severe re-

tardation, such as lissencephaly and schizencephaly. As to thegenetic counselling of parents of children with brain malforma-

tions, rvhich can not be attributed to a specific syndrome, the

empirical recurrence risk is of the order of 2-4 %o (3). The possi-

bility of a prenatal diagnosis of cerebral malformations by ultra

sound should be considered in future pregnancies.

The interpretation of N'IRI findings in group Crvas difficult for various reasons. One of these u'as the fact thatvolumetric measurement of the brain size, padicularly the fron

tal lobes, is not yet possible at our department and that quanti-

tative assessment of white matter and gyral patterns is not yet

available. Furthermore, the longterm significance of smallpatchy hyperintense (in T2-rveighted images) u'hite matter le-

sions is not yet knou'n. In our experience these mild maturation-

al delays may be obsen'ed in apparently healthy children. Hor'l'-

ever, in the present study, these delays rvere unusually pro-

nounced. Finalty in the individual situation the significance of

isolated structural abnormalities, such as hypoplasia of corpus

callosum, megacisterna magna or enlarged supravermian cis

tern, is difficult to judge.

Our clinical findings indicate that data ob

tained from MRI is of some significance: seven out of the eight

children in this group had varying degrees of developmentalproblems and five of them showed cerebral palsy. There was

only one child rvithout neurodevelopmental problems.

The example in group D illustrates normal

N{I{I despite neurodevelopmental delays in two of the three chil-

dren.In the majority of the infants MRI revealed ab-

normalities such as migration disorders, callosal malforma-

Neuropediattics 22 ( 1991 ) 189

tions, structurai abnormalities in the posterior fossa andmyelination disorders. These are u'ell known to be more evidentin N4ltI than in CT or ultrasound (5, 7), so that NII{I appears toprovide significantll' more information in the er,aluation ofmicrocephaly.

We conclude that in microcephalic childrenu'ith neurode\.elopmental disturbances NIRI reveals morphological changes in at least two thirds of the children. Our studydoes not provide any information on the frequency of morpho-logical changes in microcephalic, but normally developed chil-dren. In these children morphological changes are likely to beless frequently obsen.ed.

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